Novel 1-aryl-3-azabicyclo[3.1.0]hexanes: preparation and use to treat neuropsychiatric disorders

ABSTRACT

The invention provides novel, multiply-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including depression and anxiety.

REFERENCE TO RELATED APPLICATION

This application is related to and claims priority from U.S. ProvisionalApplication 60/703,364 filed on Jul. 27, 2005, the disclosure of whichis incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to novel1-aryl-3-azabicyclo[3.1.0]hexanes, intermediates and methods for theproduction thereof, and their use for treating disorders of the centralnervous system (CNS), including neuropsychiatric disorders.

BACKGROUND OF THE INVENTION

1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane has been reported toinhibit reuptake of norepinephrine, serotonin and dopamine—threebiogenic amines that have been implicated in a wide variety ofneuropsychiatric disorders ranging from anxiety and depression to eatingdisorders and drug addiction. One potential use of1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is as anantidepressant. The ability of this compound to inhibit reuptake ofthree biogenic amines closely linked to depression suggests a possibleuse of the compound as a “broad spectrum antidepressant.” In thiscontext, compounds having such activity may yield a more rapid onsetand/or higher efficacy of antidepressant activity than currentlyavailable antidepressants, including agents that inhibit single or dualreuptake of serotonin and/or norepinephrine [Skolnick, P. et al., Eur.J. Pharmacol. 461: 99 (2003); Skolnick, P. et al., Life Sci. 73:3175-3179, (2003)].

In view of the limited availability and understanding of currently-known“broad spectrum antidepressants,” there remains a compelling need in theart to identify additional drugs having multiple reuptake inhibitorypotential for inhibiting reuptake of multiple biogenic amines linked todisorders of the central nervous system (CNS), includingneuropsychiatric disorders, such as depression and anxiety.

Summary of Exemplary Embodiments of the Invention

It is therefore an object of the present invention to provide novelcompounds having activity to inhibit reuptake of multiple biogenicamines linked to CNS disorders, and to provide related compositions, andmethods for treating and managing CNS disorders, including depressionand anxiety.

It is a further object of the present invention to produce and selectnovel 1-aryl-3-azabicyclo[3.1.0]hexanes as therapeutic agents.

It is another object of the invention to provide new synthetic methodsand compositions useful for producing 1-aryl-3-azabicyclo[3.1.0]hexanesand related compounds.

It is an additional object of the invention to provide novel1-aryl-3-azabicyclo[3.1.0]hexane compositions and methods useful totreat or manage CNS disorders by modulating transport of one or morebiogenic amines, for example to simultaneously inhibit or block reuptakeof norepinephrine and/or serotonin and/or dopamine.

The invention achieves these objects and satisfies additional objectsand advantages by providing novel 1-aryl-3-azabicyclo[3.1.0]hexanes thatpossess unexpected activities for modulating biogenic amine transport.

In certain embodiments of the invention, novel1-aryl-3-azabicyclo[3.1.0]hexanes are provided that have at least twosubstituents on the aryl ring.

In other embodiments of the invention, novel1-aryl-3-azabicyclo[3.1.0]hexanes are provided that are substituted witha napthyl group on the nitrogen at the ‘3’ position.

In exemplary embodiments, novel 1-aryl-3-azabicyclo[3.1.0]hexanes of theinvention are provided having the following formula I:

and enantiomers and pharmaceutically acceptable salts thereof, wherein:Ar is a phenyl group substituted with two substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino;R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; andR₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; with the provisothat when Ar is 3,4-dichlorophenyl, R₃ cannot be hydrogen.

In further embodiments, the invention provides compounds of thefollowing formula II:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;R₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; andR₄ and R₅ are independently hydrogen or 1-4 substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.

In additional embodiments, the invention provides compounds of thefollowing formula III:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;R₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; andR₄ and R₅ are independently hydrogen or 1-4 substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.

Useful 1-aryl-3-azabicyclo[3.1.0]hexanes of the invention include thesubstituted 1-aryl-3-azabicyclo[3.1.0]hexanes compounds describedherein, as well as their active, pharmaceutically acceptable salts,polymorphs, solvates, hydrates and or prodrugs, or combinations thereof.

The invention also provides novel methods of making1-aryl-3-azabicyclo[3.1.0]hexanes, including synthetic methods that formnovel intermediate compounds of the invention for producing1-aryl-3-azabicyclo[3.1.0]hexanes. In related embodiments, the inventionprovides novel processes for preparing1-aryl-3-azabicyclo[3.1.0]hexanes, to yield novel compounds useful inbiologically active and/or therapeutic compositions.

In yet additional embodiments, the invention provides pharmaceuticalcompositions and methods for treating disorders of the central nervoussystem (CNS), including a wide array of serious neurological orpsychiatric conditions, in mammals that are amenable to treatment usingagents that inhibit or otherwise modulate biogenic amine transport.

The foregoing objects and additional objects, features, aspects andadvantages of the present invention are further exemplified anddescribed in the following detailed description.

Detailed Description of Exemplary Embodiments of the Invention

The present invention fulfills these needs and satisfies additionalobjects and advantages by providing novel1-aryl-3-azabicyclo[3.1.0]hexanes as therapeutic agents to treat andmanage a wide variety of disorders of the central nervous system (CNS),including neuropsychiatric disorders. CNS disorders for treatment usingthe compositions and methods of the invention are amenable to treatment,prophylaxis, and/or alleviation of the disorder and/or associatedsymptom(s) by inhibiting reuptake of multiple biogenic amines causallylinked to the targeted CNS disorder, wherein the biogenic aminestargeted for reuptake inhibition are selected from norepinephrine,and/or serotonin, and/or dopamine. In exemplary embodiments, the novelcompounds of the invention are employed in effective compositions andmethods for treating a neuropsychiatric disorder, such as depression oranxiety.

In one embodiment, the invention provides compounds of the followingformula I:

and enantiomers and pharmaceutically acceptable salts thereof, wherein:Ar is a phenyl group substituted with two substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino;R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; andR₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; with the provisothat when Ar is 3,4-dichlorophenyl, R₃ cannot be hydrogen.

In certain embodiments, Ar is a phenyl group substituted with twosubstituents independently selected from methyl, ethyl, fluoro, chloro,trifluoromethyl, cyano, nitro, and trifluoromethoxy. In additionalembodiments, R₁ and R₂ are hydrogen or methyl and R₃ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl orcyclopropyl.

In another embodiment, the invention provides compounds of the followingformula II:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;R₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; andR₄ and R₅ are independently hydrogen or 1-4 substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.

In certain embodiments, R₄ and R₅ are independently hydrogen or 1-4substituents independently selected from methyl, ethyl, fluoro, chloro,trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy. Inadditional embodiments, R₁ and R₂ are hydrogen, R₃ is hydrogen, methyl,ethyl or isopropyl and R₄ and R₅ are independently selected fromhydrogen, methyl, chloro, fluoro, propyl, methoxy and ethoxy.

In a further embodiment, the invention provides compounds of thefollowing formula III:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy;R₃ is selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉ cycloalkanoyl, aryl, heteroaryl,saturated heterocyclic, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, and substitutedC₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀ alkynyl wherein the substituent isone or more of cyano, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy, C₁₋₆ alkanoyl, C₁₋₆alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy, C₄₋₉ cycloalkanoyl,aryl, aryloxy, heteroaryl and saturated heterocyclic; andR₄ and R₅ are independently hydrogen or 1-4 substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.

In certain embodiments, R₄ and R₅ are independently hydrogen or 1-4substituents independently selected from methyl, ethyl, fluoro, chloro,trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy. Inadditional embodiments, R₁ and R₂ are hydrogen, R₃ is hydrogen, methyl,ethyl or isopropyl and R₄ and R₅ are independently selected fromhydrogen, methyl, chloro, fluoro, propyl, methoxy and ethoxy.

Within exemplary embodiments, the invention provides an assemblage ofnovel 1-aryl-3-azabicyclo[3.1.0]hexanes having multiple substitutions onthe aryl ring. Novel, multiply aryl-substituted,1-aryl-3-azabicyclo[3.1.0]hexanes of the invention include thefollowing, exemplary compounds, which have been made and characterizedas illustrative embodiments of the invention (Table 1). TABLE 1Exemplary 1-aryl-3-azabicyclo[3.1.0] hexanes having multiplesubstitutions on the aryl ring

1-(2,4-difluoroplenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

3-ethyl-1-(2,4-dfluorophenyl)- 3-aza-bicyclo[3.1.0]hexane

1-(2,4-difluorophenyl)-3-ispropyl- 3-aza-bicyclo[3.1.0]hexane

1-(3,4-difluorophenyl)-3- aza-bicyclo[3.1.0]hexane

1-(3,4-difluorophenyl)-3-methyl- 3-aza-bicyclo[3.1.0]hexane

1-(3,4-difluorophenyl)-3-ethyl- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-3-ethyl-1-(3,4-difluorophenyl)- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-3-ethyl-1-(3,4-difluorophenyl)- 3-aza-bicyclo[3.1.0]hexane

1-(3,4-difluorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane

1-[3-chloro-4-fluorophenyl)- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-chloro-4-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-chloro-4-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane

1-(3-chloro-4-fluorophenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3-chloro-4-fluorophenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-chloro-4-fluorophenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

1-(3-chloro-4-fluorophenyl)-3-ethyl-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3-chloro-4-fluorophenyl)-3- ethyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-chloro-4-fluorophenyl)-3- ethyl-3-aza-bicyclo[3.1.0]hexane

1-(3-chloro-4-fluorophenyl)-3-isopropyl-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(4-chloro-3-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(4-chloro-3-fluorophenyl)-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(4-chloro-3-fluorophenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-(4-chloro-3-fluorophenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

1-(2,4-dichlorophenyl)-3-methyl-3-aza- bicyclo[3.1.0]hexane

1-(2,4-dichlorophenyl)-3-ethyl-3-aza- bicyclo[3.1.0]hexane

1-(2,4-dichlorophenyl)-3-isopropyl-3- aza-bicyclo[3.1.0]hexane

1-(4-fluoro-3-methylphenyl)-3-aza- bicyclo[3.1.0]hexane

1-(4-fluoro-3-methylphenyl)-3-methyl-3-aza- bicyclo[3.1.0]hexane

3-ethyl-1-(4-fluoro-3-methylphenyl)-3- aza-bicyclo[3.1.0]hexane

1-(4-fluoro-3-methylphenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane

1-(3-fluoro-4-methylphenyl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-1-(3-fluoro-4-methylphenyl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-fluoro-4-methylphenyl)-3- aza-bicyclo[3.1.0]hexane

1-(3-fluoro-4-methylphenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3-fluoro-4-methylphenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3-fluoro-4-methylphenyl)-3- methyl-3-aza-bicyclo[3.1.0]hexane

1-(3-fluoro-4-methylphenyl)-3-ethyl-3-aza- bicyclo[3.1.0]hexane

1-(3-fluoro-4-methylphenyl)-3-ispropyl-3- aza-bicyclo[3.1.0]hexane

1-(3-fluoro-4-methoxyphenyl)-3-aza- bicyclo[3.1.0]hexane

1-(3-fluoro-4-(trifluommethoxy)phenyl)- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane

1-(3-chloro-4-nitrophenyl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane

(1S,5R)-1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane

3-methyl-1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-3-methyl-1-(naphthalen-1-yl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza- bicyclo[3.1.0]hexane

1-(1-fluoronaphthalen-4-yl)-3-aza- bicyclo[3.1.0]hexane

1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza- bicyclo[3.1.0]hexane

1-(1-methylnaphthalen-4-yl)-3-aza- bicyclo[3.1.0]hexane

3-methyl-1-(1-methylnaphthalen-4-yl)-3- aza-bicyclo[3.1.0]hexane

1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

(1S,5R)-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

3-methyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-3-methyl-1-(naphthalen-2-yl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

3-ethyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

3-isopropyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

(1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza- bicyclo[3.1.0]hexane

(1S,5R)-3-isopropyl-1-(naphthalen-2-yl)- 3-aza-bicyclo[3.1.0]hexane

1-(2-methoxynaphthalen-6-yl)-3-aza- bicyclo[3.1.0]hexane

1-(2-methoxynaphthalen-6-yl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

1-(2-ethoxynaphthalen-6-yl)-3-aza- bicyclo[3.1.0]hexane

1-(2-ethoxynaphthalen-6-yl)-3-methyl-3- aza-bicyclo[3.1.0]hexane

Cis-1-(3,4-dichlorophenyl)-2-methyl-3- aza-bicyclo[3.1.0]hexane

Cis-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza- bicyclo[3.1.0]hexane

Trans-1-(3,4-dichlorophenyl)-2-methyl-3-aza- bicyclo[3.1.0]hexane

Trans-1-(3,4-dichlorophenyl)-2,3-dimethyl-3- aza-bicyclo[3.1.0]hexane

Cis-1-(3,4-dichlorophenyl)-4-methyl-3-aza- bicyclo[3.1.0]hexane

Trans-1-(3,4-dichlorophenyl)-4-methyl- 3-aza-bicyclo[3.1.0]hexane

Trans-1-(3,4-dichlorophenyl)-3,4- dimethyl-3-aza-bicyclo[3.1.0]hexane

It will be understood that the exemplary, multiply aryl-substitutedcompounds identified in Table 1 are illustrative, and that the subjectmodifications comprising multiple aryl substitutions can be varied tocomprise other substituents, can include yet additional substituents(e.g., three or more substitutions on the aryl ring), combined with oneanother, or additionally combined with one or more substitutions on theazabicyclo[3.1.0]hexane ring, to yield yet additional compounds withinthe invention for treating CNS disorders (including a range ofneuropsychiatric disorders, such as depression and anxiety). Forexample, the invention provides an illustrative assemblage of novel1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanes having multiplesubstitutions, (e.g., as illustrated by multiple chloro substitutions)on the aryl ring, combined with a substitution on the nitrogen(alternatively, an “aza substitution”) at the ‘3’ position. Novel1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexanes of the inventionhaving a substitution on the nitrogen at the ‘3’ position of theinvention include the following, exemplary compounds, which have beenmade and characterized as illustrative embodiments of the invention(Table 2). The subject compounds are depicted as hydrochloride salts,whereas it will be understood that the invention encompasses all formsof the compounds as described herein, including free base forms, and allpharmaceutically acceptable salts, polymorphs, solvates, hydrates, andprodrugs thereof: TABLE 2 Exemplary 1-aryl-3-azabicyclo[3.1.0] hexaneshaving multiple substitutions on the aryl ring combined with an azasubstitution

(1R,5S)-1-(3,4-dichlorophenyl)-3-methyl- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorophenyl)-3-methyl- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3- aza-bicyclo[3.1.0]hexane

1-(3,4-dichlorophenyl)-3-propyl-3- aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3,4-dichlorophenyl)-3-propyl- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorophenyl)-3-propyl- 3-aza-bicyclo[3.1.0]hexane

1-(3,4-dichlorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3,4-dichlorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl- 3-aza-bicyclo[3.1.0]hexane

1-(3,4-dichlorophenyl)-3-cyclopropyl- 3-aza-bicyclo(3.1.0]hexane

(1R,5S)-1-(3,4-dichlorophenyl)-3-cyclopropyl- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorphenyl)-3-cyclopropyl- 3-aza-bicyclo[3.1.0]hexane

3-butyl-1-(3,4-dichlorophenyl)- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-3-butyl-1-(3,4-dichlorophenyl)-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-3-butyl-1-(3,4-dichlorophenyl)-3- aza-bicyclo[3.1.0]hexane

1-(3,4-dichlorophenyl)-3-isobutyl- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-1-(3,4-dichlorophenyl)-3-isobutyl-3- aza-bicyclo[3.1.0]hexane

(1S,5R)-1-(3,4-dichlorophenyl)-3-isobutyl-3- aza-bicyclo[3.1.0]hexane

3-tert-butyl-1-(3,4-dichlorophenyl)- 3-aza-bicyclo[3.1.0]hexane

(1R,5S)-3-tert-butyl-1-(3,4-dichlorophenyl)- 3-aza-bicyclo[3.1.0]hexane

(1S,5R)-3-tert-butyl-1-(3,4-dichlorophenyl)-3- aza-bicyclo[3.1.0]hexane

Within related aspects of the invention, enantiomeric forms of the novelcompounds described herein, having chiral symmetric structure, areprovided, which provide yet additional drug candidates for treating CNSdisorders. In certain embodiments, the invention provides enantiomers,diastereomers, and other stereoisomeric forms of the disclosedcompounds, including racemic and resolved forms and mixtures thereof.The individual enantiomers may be separated according to methods thatare well known to those of ordinary skill in the art. In certainembodiments, the enantiomers, diastereomers and other stereoisomericforms of the disclosed compounds are substantially free of thecorresponding enantiomers, diastereomers and stereoisomers. In otherembodiments, the enantiomers, diastereomers and other stereoisomericforms of the disclosed compounds contain no more than about 10%, about5%, about 2% or about 1% of the corresponding enantiomers, diastereomersand stereoisomers. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended to include both E and Z geometricisomers. All tautomers are intended to be encompassed by the presentinvention as well.

As noted above, the compounds of the present invention can be preparedas both acid addition salts formed from an acid and the basic nitrogengroup of 1-aryl-3-azabicyclo[3.1.0]hexanes and base salts. As furthernoted below, the methods of the present invention can be used to preparecompounds as both acid addition salts formed from an acid and the basicnitrogen group of 1-aryl-3-azabicyclo[3.1.0]hexanes and base salts.Suitable acid addition salts are formed from acids which form non-toxicsalts and include, for example, hydrochloride, hydrobromide,hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, andhydrogen phosphate salts. Other examples of pharmaceutically acceptableaddition salts include inorganic and organic acid addition salts.Additional pharmaceutically acceptable salts include, but are notlimited to, metal salts such as sodium salt, potassium salt, cesium saltand the like; alkaline earth metals such as calcium salt, magnesium saltand the like; organic amine salts such as triethylamine salt, pyridinesalt, picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;organic acid salts such as acetate, citrate, lactate, succinate,tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate,trifluoroacetate, oxalate, formate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; andamino acid salts such as arginate, asparginate, glutamate, tartrate,gluconate and the like. Suitable base salts are formed from bases whichform non-toxic salts and include, for example, aluminum, calcium,lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

In other detailed embodiments, the invention provides prodrugs of thedisclosed compounds. Prodrugs are considered to be any covalently bondedcarriers which release the active parent drug in vivo. Examples ofprodrugs include esters or amides of a compound of the present inventionwith hydroxyalkyl or aminoalkyl as a substituent. These may be preparedby reacting such compounds with anhydrides such as succinic anhydride.

The invention disclosed herein will also be understood to encompass invivo metabolic products of the disclosed compounds. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

The invention disclosed herein will also be understood to encompass thedisclosed compounds isotopically-labelled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively.

The compounds of the instant invention may be prepared using methodsknown to those skilled in the art, and in other embodiments by employingnovel synthetic schemes as provided herein, which, along with theexemplified intermediate compounds, also fall within the scope of theinvention. Accordingly, the present invention also provides novelmethods and compositions for producing the compounds of the presentinvention as well as other 1-aryl-3-azabicyclo[3.1.0]hexanes.

In certain embodiments, the present invention provides methods formaking a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula IV,

wherein Ar is a phenyl group substituted with two substituentsindependently selected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino,an unsubstituted napthyl group or a napthyl group having 1-4substituents independently selected from halogen, C₁₋₃ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl,C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino,and enantiomers and diastereomers thereof, comprising the steps of:

-   -   (a) reacting a compound of the following formula (i),    -   wherein Ar is defined as above, with epichlohydrin or an        enantiomer thereof, to produce a compound of the following        formula (ii),    -    or an enantiomer or diastereomer thereof;    -   (b) reducing the compound of formula (ii) to produce a compound        of the following formula (iii),    -    , or an enantiomer or diastereomer thereof;    -   (c) causing cyclization of the compound of formula (iii) to        produce the 1-aryl-3-azabicyclo[3.1.0]hexane, or an enantiomer        or diastereomer thereof.

In other embodiments, the present invention provides methods for makinga 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula IV,

wherein Ar is a phenyl group substituted with two substituentsindependently selected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino,an unsubstituted napthyl group or a napthyl group having 1-4substituents independently selected from halogen, C₁₋₃ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl,C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino; and di(C₁₋₃)alkylamino,and enantiomers and diastereomers thereof, comprising the steps of:

-   -   (a) reacting a compound of the following formula (i),    -   wherein Ar is defined as above, with epichlohydrin to produce a        compound of the following    -   (b) reducing the compound of formula (ii) to produce a compound        of the following formula (iii),    -   (c) reacting the compound of formula (iii) with (Boc)₂O to        produce a compound of the following formula (iv),    -   (d) causing cyclization of the compound of formula (iv) to        produce a compound of the following formula (v),    -   (e) deprotecting the compound of formula (v) to produce a        compound of the following formula (vi),    -    and    -   (f) reducing the compound of formula (vi) to produce the        1-aryl-3-azabicyclo[3.1.0]hexane.

In additional embodiments, the present invention provides methods ofmaking a 1-aryl-3-azabicyclo[3.1.0]hexane of the following formula V,

wherein Ar is a phenyl group substituted with two substituentsindependently selected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino,an unsubstituted napthyl group or a napthyl group having 1-4substituents independently selected from halogen, C₁₋₃ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl,C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino,and R is hydrogen, methyl, ethyl, isopropyl or a nitrogen protectinggroup, and enantiomers and diastereomers thereof, comprising the stepsof:

-   -   (a) reacting a compound of the following formula (vii),    -    wherein R is as defined above, with    -    wherein Ar is as defined above, to produce a compound of the        following formula (viii),    -   (b) causing cyclopropanation of the compound of formula (viii)        to produce a compound of the following formula (ix),    -    and    -   (c) reducing the compound of formula (ix) to produce the        1-aryl-3-azabicyclo[3.1.0]hexane.

In practicing the methods of the present for methods for making1-aryl-3-azabicyclo[3.1.0]hexanes, various reagents may be utilized forthe different reaction steps. In general, suitable reagents for thevarious reaction steps may be selected by one of ordinary skill in theart based on the present disclosure.

Suitable reducing agents and methodologies include, for example, lithiumaluminum hydride (LAH), sodium aluminum hydride (SAH), NaBH₄ with ZnCl₂and catalytic hydrogenation.

Suitable nitrogen protecting groups include, for example, benzyl, allyl,tert-butyl and 3,4-dimethoxy-benzyl groups. In general, nitrogenprotecting groups are well known to those skilled in the art, see forexample, “Nitrogen Protecting Groups in Organic Synthesis”, John Wileyand Sons, New York, N.Y., 1981, Chapter 7; “Nitrogen Protecting Groupsin Organic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2; T.W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry”,3rd edition, John Wiley & Sons, New York, N.Y., 1999.

When the nitrogen protecting group is no longer needed, it may beremoved by methods well known in the art. For example, benzyl or3,4-dimethoxy-benzyl groups may be removed by catalytic hydrogenation.In general, methods of removing nitrogen protecting groups are wellknown to those skilled in the art, see for example, “Nitrogen ProtectingGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1981,Chapter 7; “Nitrogen Protecting Groups in Organic Chemistry”, PlenumPress, New York, N.Y., 1973, Chapter 2; T. W. Green and P. G. M. Wuts in“Protective Groups in Organic Chemistry”, 3rd edition, John Wiley &Sons, Inc. New York, N.Y., 1999.

Suitable reagents for causing cyclization include, for example, SOCl₂,POCl₃, oxalyl chloride, phosphorous tribromide, triphenylphosphorousdibromide and oxalyl bromide.

Exemplary synthetic methods, starting materials, and intermediatesuseful in various aspects of the invention for producing novel compoundsof the present invention are described in the examples.

For the purposes of describing the invention, including the novelcompounds and synthetic methods disclosed herein, the following termsand definitions are provided by way of example.

The term “halogen” as used herein refers to bromine, chlorine, fluorineor iodine. In one embodiment, the halogen is chlorine. In anotherembodiment, the halogen is bromine.

The term “hydroxy” as used herein refers to —OH or —O⁻.

The term “alkyl” as used herein refers to straight- or branched-chainaliphatic groups containing 1-20 carbon atoms, preferably 1-7 carbonatoms and most preferably 1-4 carbon atoms. This definition applies aswell to the alkyl portion of alkoxy, alkanoyl and aralkyl groups. In oneembodiment, the alkyl is a methyl group.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. In oneembodiment, the alkoxy group contains 1 to 4 carbon atoms. Embodimentsof alkoxy groups include, but are not limited to, methoxy, ethoxy,isopropyloxy, propoxy, butoxy, and pentoxy groups. Embodiments ofsubstituted alkoxy groups include halogenated alkoxy groups. In afurther embodiment, the alkoxy groups can be substituted with groupssuch as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Exemplary halogen substituted alkoxy groupsinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

The term “nitro”, as used herein alone or in combination, refers to a—NO₂ group.

The term “amino” as used herein refers to the group —NRR′, where R′ andR′ may independently be hydrogen, alkyl, aryl, alkoxy, or heteroaryl.The term “aminoalkyl” as used herein represents a more detailedselection as compared to “amino” and refers to the group —NRR′, where Rand R′ may independently be hydrogen or (C₁-C₄)alkyl.

The term “trifluoromethyl” as used herein refers to —CF₃.

The term “trifluoromethoxy” as used herein refers to —OCF₃.

The term “cycloalkyl” as used herein refers to a saturated cyclichydrocarbon ring system containing from 3 to 7 carbon atoms that may beoptionally substituted. Exemplary embodiments include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Incertain embodiments, the cycloalkyl group is cyclopropyl. In anotherembodiment, the (cycloalkyl)alkyl groups contain from 3 to 7 carbonatoms in the cyclic portion and 1 to 4 carbon atoms in the alkylportion. In certain embodiments, the (cycloalkyl)alkyl group iscyclopropylmethyl. The alkyl groups are optionally substituted with fromone to three substituents selected from the group consisting of halogen,hydroxy and amino.

The terms “alkanoyl” and “alkanoyloxy” as used herein refer,respectively, to —C(O)-alkyl groups and —O—C(O)-alkyl groups, eachoptionally containing 2-5 carbon atoms. Specific embodiments of alkanoyland alkanoyloxy groups are acetyl and acetoxy, respectively.

The term “aryl” as used herein refers to monocyclic or bicyclic aromatichydrocarbon groups having from 6 to 12 carbon atoms in the ring portion,for example, phenyl, naphthyl, biphenyl and diphenyl groups, each ofwhich may be substituted with, for example, one to four substituentssuch as alkyl, substituted alkyl as defined above, halogen,trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy,alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, nitro, cyano,carboxy, carboxyalkyl, carbamyl, carbamoyl and aryloxy. Specificembodiments of aryl groups in accordance with the present inventioninclude phenyl, substituted phenyl, naphthyl, biphenyl, and diphenyl.

The term “aroyl,” as used alone or in combination herein, refers to anaryl radical derived from an aromatic carboxylic acid, such asoptionally substituted benzoic or naphthoic acids.

The term “aralkyl” as used herein refers to an aryl group bonded to the4-pyridinyl ring through an alkyl group, preferably one containing 1-4carbon atoms. A preferred aralkyl group is benzyl.

The term “nitrile” or “cyano” as used herein refers to the group —CN.

The term “dialkylamino” refers to an amino group having two attachedalkyl groups that can be the same or different.

The term “alkenyl” refers to a straight or branched alkenyl group of 2to 10 carbon atoms having 1 to 3 double bonds. Preferred embodimentsinclude ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl,4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 1-heptenyl,2-heptenyl, 1-octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl,1,3-nonadienyl, 2-decenyl, etc.

The term “alkynyl” as used herein refers to a straight or branchedalkynyl group of 2 to 10 carbon atoms having 1 to 3 triple bonds.Exemplary alkynyls include, but are not limited to, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,4-pentynyl, 1-octynyl, 6-methyl-1-heptynyl, and 2-decynyl.

The term “hydroxyalkyl” alone or in combination, refers to an alkylgroup as previously defined, wherein one or several hydrogen atoms,preferably one hydrogen atom has been replaced by a hydroxyl group.Examples include hydroxymethyl, hydroxyethyl and 2-hydroxyethyl.

The term “aminoalkyl” as used herein refers to the group —NRR′, where Rand R′ may independently be hydrogen or (C₁-C₄)alkyl.

The term “alkylaminoalkyl” refers to an alkylamino group linked via analkyl group (i.e., a group having the general structure —alkyl-NH-alkylor —alkyl-N(alkyl)(alkyl)). Such groups include, but are not limited to,mono- and di-(C₁-C₈ alkyl)aminoC₁-C₈ alkyl, in which each alkyl may bethe same or different.

The term “dialkylaminoalkyl” refers to alkylamino groups attached to analkyl group. Examples include, but are not limited to,N,N-dimethylaminomethyl, N,N-dimethylaminoethyl,N,N-dimethylaminopropyl, and the like. The term dialkylaminoalkyl alsoincludes groups where the bridging alkyl moiety is optionallysubstituted.

The term “haloalkyl” refers to an alkyl group substituted with one ormore halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like.

The term “carboxyalkyl” as used herein refers to the substituent—R′—COOH wherein R′ is alkylene; and carbalkoxyalkyl refers to —R′—COORwherein R′ and R are alkylene and alkyl respectively. In certainembodiments, alkyl refers to a saturated straight- or branched-chainhydrocarbyl radical of 1-6 carbon atoms such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, n-pentyl, 2-methylpentyl, n-hexyl, and soforth. Alkylene is the same as alkyl except that the group is divalent.

The term “alkoxyalkyl” refers to an alkylene group substituted with analkoxy group. For example, methoxyethyl [CH₃OCH₂CH₂—] and ethoxymethyl(CH₃CH₂OCH₂—] are both C₃ alkoxyalkyl groups.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “alkanoylamino” refers to alkyl, alkenyl or alkynyl groupscontaining the group —C(O)— followed by —N(H)—, for example acetylamino,propanoylamino and butanoylamino and the like.

The term “carbonylamino” refers to the group —NR—CO—CH₂—R′, where R andR′ may be independently selected from hydrogen or (C₁-C₄)alkyl.

The term “carbamoyl” as used herein refers to —O—C(O)NH₂.

The term “carbamyl” as used herein refers to a functional group in whicha nitrogen atom is directly bonded to a carbonyl, i.e., as in —NRC(═O)R′or —C(═O)NRR′, wherein R and R′ can be hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl,heterocyclo, or heteroaryl.

The term “heterocyclo” refers to an optionally substituted, unsaturated,partially saturated, or fully saturated, aromatic or nonaromatic cyclicgroup that is a 4 to 7 membered monocyclic, or 7 to 11 membered bicyclicring system that has at least one heteroatom in at least one carbonatom-containing ring. The substituents on the heterocyclo rings may beselected from those given above for the aryl groups. Each ring of theheterocyclo group containing a heteroatom may have 1, 2 or 3 heteroatomsselected from nitrogen atoms, oxygen atoms and sulfur atoms. Pluralheteroatoms in a given heterocyclo ring may be the same or different.The heterocyclo group may be attached to the 4-pyridinyl ring at anyheteroatom or carbon atom. In one embodiment, two R groups form a fusedring with the carbons at position 2 and 3 of the pyridinyl ring, thereis formed a 7-quinolin-4-yl moiety.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

In additional embodiments, the invention provides pharmaceuticalcompositions and methods for treating CNS disorders, including but notlimited to neuropsychiatric conditions, such as depression and anxiety.Suitable forms of the compounds of the invention for use in biologicallyactive compositions and methods of the invention include the compoundsexemplified herein, as well as their pharmaceutically acceptable salts,polymorphs, solvates, hydrates, and prodrugs.

Within related embodiments, the invention provides methods for treatingCNS disorders responsive to the inhibition of biogenic aminetransporters, in particular, one or more, or any combination of, thenorepinephrine, serotonin and dopamine transporters, in mammaliansubjects. In more detailed embodiments, the invention provides methodsfor using the novel compounds disclosed herein for treating CNSdisorders, including a range of neuropsychiatric disorders, such asdepression and anxiety. In various embodiments, the compositions andmethods are formulated, and administered, effectively asanti-depressants, or as anxiolytic agents.

In accordance with the invention, compounds disclosed herein, optionallyformulated with additional ingredients in a pharmaceutically acceptablecomposition, are administered to mammalian subjects, for example a humanpatient, to treat or prevent one or more symptom(s) of a CNS disorderalleviated by inhibiting dopamine reuptake, and/or norepinephrinereuptake, and/or serotonin reuptake. In certain embodiments, “treatment”or “treating” refers to amelioration of one or more symptom(s) of a CNSdisorder, whereby the symptom(s) is/are alleviated by inhibitingdopamine and/or norepinephrine and/or serotonin reuptake. In otherembodiments, “treatment” or “treating” refers to an amelioration of atleast one measurable physical parameter associated with a CNS disorder.In yet another embodiment, “treatment” or “treating” refers toinhibiting or reducing the progression or severity of a CNS disorder (orone or more symptom(s) thereof) alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake, e.g., as discerned based onphysical, physiological, and/or psychological parameters. In additionalembodiments, “treatment” or “treating” refers to delaying the onset of aCNS disorder (or one or more symptom(s) thereof) alleviated byinhibiting dopamine and/or norepinephrine and/or serotonin reuptake.

In certain embodiments, a compound of the present invention or apharmaceutically acceptable salt thereof is administered to a mammaliansubject, for example a human patient, as a preventative or prophylactictreatment against a CNS disorder (or one or more symptom(s) thereof)alleviated by inhibiting dopamine and/or norepinephrine and/or serotoninreuptake. As used herein, “prevention”, “preventing”, and prophylaxisrefers to a reduction in the risk or likelihood that the subject willacquire a CNS disorder or one or more symptom(s) thereof, which risk orlikelihood is reduced in the subject by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake. Alternatively, prevention andprophylaxis may correlate with a reduced risk of recurrence of the CNSdisorder or symptom(s) thereof in the subject once the subject has beencured, restored to a normal state, or placed in remission from thesubject CNS disorder. In related embodiments, a compound orpharmaceutical composition of the invention is administered as apreventative measure to the subject. Exemplary subjects amenable toprophylactic treatment in this context may have a genetic predispositionto a CNS disorder amenable to treatment by inhibiting dopamine, and/orserotonin, and/or norepinephrine reuptake, such as a family history of abiochemical imbalance in the brain, or a non-genetic predisposition to adisorder alleviated by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake.

A compound of the present invention and pharmaceutically acceptablesalts thereof are useful for treating or preventing endogenous disordersalleviated by inhibiting dopamine and/or norepinephrine and/or serotoninreuptake. Such disorders include, but are not limited to,attention-deficit disorder, depression, anxiety, obesity, Parkinson'sdisease, tic disorders, and addictive disorders.

Disorders alleviated by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake are not limited to the specific disorders describedherein, and the compositions and methods of the invention will beunderstood or readily ascertained to provide effective treatment agentsfor treating and/or preventing a wide range of additional CNS disordersand associated symptoms. For example, the compounds of the inventionwill provide promising candidates for treatment and/or prevention ofattention deficit hyperactivity disorder and related symptoms, as wellas forms and symptoms of alcohol abuse, drug abuse, obsessive compulsivebehaviors, learning disorders, reading problems, gambling addiction,manic symptoms, phobias, panic attacks, oppositional defiant behavior,conduct disorder, academic problems in school, smoking, abnormal sexualbehaviors, schizoid behaviors, somatization, depression, sleepdisorders, general anxiety, stuttering, and tics disorders (see forexample, U.S. Pat. No. 6,132,724). These and other symptoms, regardlessof the underlying CNS disorder, are each prospective therapeutic targetsfor the novel compositions and methods of the invention that mediatetherapeutic benefits by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake. Additional CNS disorders contemplated for treatmentemploying the compositions and methods of the invention are described,for example, in the Quick Reference to the Diagnostic Criteria FromDSM-IV (Diagnostic and Statistical Manual of Mental Disorders, FourthEdition), The American Psychiatric Association, Washington, D.C., 1994.These target disorders for treatment and/or prevention according to theinvention, include, but are not limited to,Attention-Deficit/Hyperactivity Disorder, Predominately InattentiveType; Attention-Deficit/Hyperactivity Disorder, PredominatelyHyperactivity-Impulsive Type; Attention-Deficit/Hyperactivity Disorder,Combined Type; Attention-Deficit/Hyperactivity Disorder not otherwisespecified (NOS); Conduct Disorder; Oppositional Defiant Disorder; andDisruptive Behavior Disorder not otherwise specified (NOS).

Depressive disorders amenable for treatment and/or prevention accordingto the invention include, but are not limited to, Major DepressiveDisorder, Recurrent; Dysthymic Disorder; Depressive Disorder nototherwise specified (NOS); and Major Depressive Disorder, SingleEpisode.

Addictive disorders amenable for treatment and/or prevention employingthe methods and compositions of the invention include, but are notlimited to, eating disorders, impulse control disorders, alcohol-relateddisorders, nicotine-related disorders, amphetamine-related disorders,cannabis-related disorders, cocaine-related disorders, hallucinogen usedisorders, inhalant-related disorders, and opioid-related disorders, allof which are further sub-classified as listed below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; and Eating Disorder nototherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder, with delusions; Alcohol Abuse;Alcohol Intoxication; Alcohol Withdrawal; Alcohol Intoxication Delirium;Alcohol Withdrawal Delirium; Alcohol-Induced Persisting Dementia;Alcohol-Induced Persisting Amnestic Disorder; Alcohol Dependence;Alcohol-Induced Psychotic Disorder, with hallucinations; Alcohol-InducedMood Disorder; Alcohol-Induced Anxiety Disorder; Alcohol-Induced SexualDysfunction; Alcohol-Induced Sleep Disorders; Alcohol-Related Disordersnot otherwise specified (NOS); Alcohol Intoxication; and AlcoholWithdrawal.

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, Amphetamine Related Disorder not otherwise specified (NOS),Amphetamine Intoxication, and Amphetamine Withdrawal.

Cannabis-related disorders include, but are not limited to, CannabisDependence; Cannabis Abuse; Cannabis Intoxication; Cannabis IntoxicationDelirium; Cannabis-Induced Psychotic Disorder, with delusions;Cannabis-Induced Psychotic Disorder with hallucinations;Cannabis-Induced Anxiety Disorder; Cannabis Related Disorder nototherwise specified (NOS); and Cannabis Intoxication.

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder,Cocaine Related Disorder not otherwise specified (NOS), CocaineIntoxication, and Cocaine Withdrawal.

Hallucinogen-use disorders include, but are not limited to, HallucinogenDependence, Hallucinogen Abuse, Hallucinogen Intoxication, HallucinogenWithdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-InducedPsychotic Disorder with delusions, Hallucinogen-Induced PsychoticDisorders with hallucinations, Hallucinogen-Induced Mood Disorder,Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced SexualDysfunction, Hallucinogen-Induced Sleep Disorder, Hallucinogen RelatedDisorder not otherwise specified (NOS), Hallucinogen Intoxication, andHallucinogen Persisting Perception Disorder (Flashbacks).

Inhalant-related disorders include, but are not limited to, InhalantDependence; Inhalant Abuse; Inhalant Intoxication; Inhalant IntoxicationDelirium; Inhalant-Induced Psychotic Disorder, with delusions;Inhalant-Induced Psychotic Disorder with hallucinations;Inhalant-Induced Anxiety Disorder; Inhalant Related Disorder nototherwise specified (NOS); and Inhalant Intoxication.

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Related Disorder not otherwise specified (NOS),Opioid Intoxication, and Opioid Withdrawal.

Tic disorders include, but are not limited to, Tourette's Disorder,Chronic Motor or Vocal Tic Disorder, Transient Tic Disorder, TicDisorder not otherwise specified (NOS), Stuttering, Autistic Disorder,and Somatization Disorder.

By virtue of their multiple reuptake inhibitory activity, the novelcompounds of the present invention are thus useful in a wide range ofveterinary and human medical applications, in particular for treatingand/or preventing a wide array of CNS disorders and/or associatedsymptom(s) alleviated by inhibiting dopamine and/or norepinephrineand/or serotonin reuptake.

Within additional aspects of the invention, combinatorial formulationsand coordinate administration methods are provided which employ aneffective amount of a compound of the invention (or a pharmaceuticallyeffective enantiomer, salt, solvate, hydrate, polymorph, or prodrugthereof), and one or more additional active agent(s) that is/arecombinatorially formulated or coordinately administered with thecompound of the invention—yielding a combinatorial formulation orcoordinate administration method that is effective to modulate,alleviate, treat or prevent a targeted CNS disorder, or one or moresymptom(s) thereof, in a mammalian subject. Exemplary combinatorialformulations and coordinate treatment methods in this context atherapeutic compound of the invention in combination with one or moreadditional or adjunctive treatment agents or methods for treating thetargeted CNS disorder or symptom(s), for example one or moreantidepressant or anxiolytic agent(s) and/or therapeutic method(s).

In related embodiments of the invention, the compounds disclosed hereincan be used in combination therapy with at least one other therapeuticagent or method. In this context, compounds of the invention can beadministered concurrently or sequentially with administration of asecond therapeutic agent, for example a second agent that acts to treator prevent the same, or different, CNS disorder or symptom(s) for whichthe compound of the invention is administered. The compound of theinvention and the second therapeutic agent can be combined in a singlecomposition or adminstered in different compositions. The secondtherapeutic agent may also be effective for treating and/or preventing aCNS disorder or associated symptom(s) by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake. The coordinate administrationmay be done simultaneously or sequentially in either order, and theremay be a time period while only one or both (or all) active therapeuticagents, individually and/or collectively, exert their biologicalactivities and therapeutic effects. A distinguishing aspect of all suchcoordinate treatment methods is that the compound of the inventionexerts at least some detectable therapeutic activity toward alleviatingor preventing the targeted CNS disorder or symptom(s), as describedherein, and/or elicit a favorable clinical response, which may or maynot be in conjunction with a secondary clinical response provided by thesecondary therapeutic agent. Often, the coordinate administration of acompound of the invention with a secondary therapeutic agent ascontemplated herein will yield an enhanced therapeutic response beyondthe therapeutic response elicited by either or both the compound of theinvention and/or secondary therapeutic agent alone.

As many of the CNS disorders and symptoms treatable or preventable usingcompounds of the present invention are chronic, in one embodimentcombination therapy involves alternating between administering acompound of the present invention and a second therapeutic agent (i.e.,alternating therapy regimens between the two drugs, e.g., at one week,one month, three month, six month, or one year intervals). Alternatingdrug regimens in this context will often reduce or even eliminateadverse side effects, such as toxicity, that may attend long-termadministration of one or both drugs alone.

In certain embodiments of combinatorial formulations and coordinatetreatment methods of the invention, the secondary therapeutic is anorepinephrine reuptake inhibitor. Examples of norepinephrine reuptakeinhibitors useful in this context include tertiary amine tricyclics suchas amitriptyline, clomipramine, doxepin, imipramine, (+)-trimipramine,and secondary amine tricyclics including amoxapine, atomoxetine,desipramine, maprotiline, nortriptyline, and protriptyline.

In certain embodiments of combinatorial formulations and coordinatetreatment methods of the invention, the secondary therapeutic is aserotonin reuptake inhibitor. Examples of other serotonin reuptakeinhibitors useful in this context include citalopram, fluoxetine,fluvoxamine, (−)-paroxetine, sertraline, and venlafaxine.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-attention-deficit-disorder treatment agent. Examples of usefulanti-attention-deficit-disorder agents for use in these embodimentsinclude, but are not limited to, methylphenidate; dextroamphetamine;tricyclic antidepressants, such as imipramine, desipramine, andnortriptyline; and psychostimulants, such as pemoline and deanol.

In additional embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-addictive-disorder agent. Examples of usefulanti-addictive-disorder agents include, but are not limited to,tricyclic antidepressants; glutamate antagonists, such as ketamine HCl,dextromethorphan, dextrorphan tartrate and dizocilpine (MK801);degrading enzymes, such as anesthetics and aspartate antagonists; GABAagonists, such as baclofen and muscimol HBr; reuptake blockers;degrading enzyme blockers; glutamate agonists, such as D-cycloserine,carboxyphenylglycine, L-glutamic acid, andcis-piperidine-2,3-dicarboxylic acid; aspartate agonists; GABAantagonists such as gabazine (SR-95531), saclofen, bicuculline,picrotoxin, and (+) apomorphine HCl; and dopamine antagonists, such asspiperone HCl, haloperidol, and (−) sulpiride.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-alcohol agent. Examples of useful anti-alcohol agents include, butare not limited to, disulfiram and naltrexone.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-nicotine agent. Examples of useful anti-nicotine agents include,but are not limited to, clonidine.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-opiate agent. Examples of useful anti-opiate agents include, butare not limited to, methadone, clonidine, lofexidine, levomethadylacetate HCl, naltrexone, and buprenorphine.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent isanti-cocaine agent. Examples of useful anti-cocaine agents include, butare not limited to, desipramine, amantadine, fluoxidine, andbuprenorphine.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-lysergic acid diethylamide (“anti-LSD”) agent. Examples of usefulanti-LSD agents include, but are not limited to, diazepam.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is ananti-phencyclidine (“anti-PCP”) agent. Examples of useful anti-PCPagents include, but are not limited to, haloperidol.

In other embodiments of combinatorial formulations and coordinatetreatment methods provided herein, the secondary therapeutic agent is anappetite suppressant. Examples of useful appetite suppressants include,but are not limited to, fenfluramine, phenylpropanolamine, and mazindol.

In yet additional embodiments of combinatorial formulations andcoordinate treatment methods provided herein, the secondary therapeuticagent is an anti-Parkinson's-disease agent. Examples of usefulanti-Parkinson's-disease agents include, but are not limited to dopamineprecursors, such as levodopa, L-phenylalanine, and L-tyrosine;neuroprotective agents; dopamine agonists; dopamine reuptake inhibitors;anticholinergics such as amantadine and memantine; and1,3,5-trisubstituted adamantanes, such as1-amino-3,5-dimethyl-adamantane (See, U.S. Pat. No. 4,122,193).

Mammalian subjects amenable for treatment according to the methods ofthe invention include, but are not limited to, human and other mammaliansubjects suffering from a CNS disorder that is amenable to treatment orbeneficial intervention using an active agent capable of inhibitingreuptake of norepinephrine, serotonin, and/or dopamine by interferingwith the CNS conditions that are subject to treatment according to themethods and compositions of the invention include depression, as well asa variety of other neuropsychiatric conditions and disorders. Otherdisorders for which the compounds of the present invention may be usefulinclude irritable bowel syndrome; inflammatory bowel disease; bulimia;anorexia; obesity and related eating disorders; urinary tract disorders,such as stress urinary incontinence; addictive disorders (includingaddiction to nicotine, stimulants, alcohol, and opiates); degenerativediseases, including Alzheimers disease, amyotrophic lateral sclerosis,and Parkinson's disease; and pyretic conditions (including fevers, andpost- and peri-menopausal hot flashes). For each of the foregoingdisorders, combinatorial formulations and coordinate treatment methodsare provided within the scope of the invention comprising compounds ofthe invention coordinately administered or combinatorially formulatedwith a second therapeutic agent or method known for treating the subjectdisorder, and/or one or more symptom(s) associated therewith.

Subjects are effectively treated prophylactically and/or therapeuticallyby administering to the subject an effective amount of a compound of theinvention, which is effective to treat, alleviate, prevent or eliminatea targeted CNS disorder in the subject, and/or one or more symptom(s)associated therewith, for example depression.

Administration of an effective amount of a compound of the presentinvention to a mammalian subject presenting with one or more of theforegoing CNS disorders and/or symptom(s) will detectably decrease,eliminate, or prevent the targeted CNS disorder and/or associatedsymptom(s). In certain embodiments, administration of a compound of thepresent invention to a suitable test subject will yield a reduction inthe targeted CNS disorder, or one or more targeted symptom(s) associatedtherewith, such as depression, by at least 10%, 20%, 30%, 50% orgreater, up to a 75-90%, or 95% or greater, reduction in the one or moretarget symptom(s), compared to placebo-treated or other suitable controlsubjects. Comparable levels of efficacy are contemplated for the entirerange of CNS disorders described herein, including all contemplatedneurological and psychiatric disorders, as well as all other CNSconditions and symptoms identified herein for treatment or preventionusing the compositions and methods of the invention.

The active compounds of the invention may be optionally formulated witha pharmaceutically acceptable carrier and/or various excipients,vehicles, stabilizers, buffers, preservatives, etc. An “effectiveamount,” “therapeutic amount,” “therapeutically effective amount,” or“effective dose” is an effective amount or dose of an active compound asdescribed herein sufficient to elicit a desired pharmacological ortherapeutic effect in a mammalian subject—typically resulting in ameasurable reduction in an occurrence, frequency, or severity of one ormore symptom(s) associated with or caused by a CNS disorder, including aneurological or psychological disease, condition, or disorder in thesubject. In certain embodiments, when a compound of the invention isadministered to treat a CNS disorder, for example depression, aneffective amount of the compound will be an amount sufficient in vivo todelay or eliminate onset of symptoms of the targeted condition ordisorder. Therapeutic efficacy can alternatively be demonstrated by adecrease in the frequency or severity of symptoms associated with thetreated condition or disorder, or by altering the nature, recurrence, orduration of symptoms associated with the treated condition or disorder.Therapeutically effective amounts, and dosage regimens, of thecompositions of the invention, including pharmaceutically effectivesalts, solvates, hydrates, polymorphs or prodrugs thereof, will bereadily determinable by those of ordinary skill in the art, often basedon routine clinical or patient-specific factors.

Suitable routes of administration for a compound of the presentinvention include, but are not limited to, oral, buccal, nasal, aerosol,topical, transdermal, mucosal, injectable, slow release, controlledrelease, iontophoresis, sonophoresis, and other conventional deliveryroutes, devices and methods. Injectable delivery methods are alsocontemplated, including but not limited to, intravenous, intramuscular,intraperitoneal, intraspinal, intrathecal, intracerebroventricular,intraarterial, and subcutaneous injection.

Suitable effective unit dosage amounts of1-aryl-3-azabicyclo[3.1.0]hexanes of the present invention for mammaliansubjects may range from about 1 to 1200 mg, 50 to 1000 mg, 75 to 900 mg,100 to 800 mg, or 150 to 600 mg. In certain embodiments, the effectiveunit dosage will be selected within narrower ranges of, for example, 10to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 150 mg, 150 to 250 mg or 250to 500 mg. These and other effective unit dosage amounts may beadministered in a single dose, or in the form of multiple daily, weeklyor monthly doses, for example in a dosing regimen comprising from 1 to5, or 2-3, doses administered per day, per week, or per month. Inexemplary embodiments, dosages of 10 to 25 mg, 30 to 50 mg, 75 to 100mg, 100 to 200 (anticipated dosage strength) mg, or 250 to 500 mg, areadministered one, two, three, or four times per day. In more detailedembodiments, dosages of 50-75 mg, 100-150 mg, 150-200 mg, 250-400 mg, or400-600 mg are administered once, twice daily or three times daily. Inalternate embodiments, dosages are calculated based on body weight, andmay be administered, for example, in amounts from about 0.5 mg/kg toabout 30 mg/kg per day, 1 mg/kg to about 15 mg/kg per day, 1 mg/kg toabout 10 mg/kg per day, 2 mg/kg to about 20 mg/kg per day, 2 mg/kg toabout 10 mg/kg per day or 3 mg/kg to about 15 mg/kg per day.

The amount, timing and mode of delivery of compositions of the inventioncomprising an effective amount of a compound of the present inventionwill be routinely adjusted on an individual basis, depending on suchfactors as weight, age, gender, and condition of the individual, theacuteness of the targeted CNS disorder and/or related symptoms, whetherthe administration is prophylactic or therapeutic, and on the basis ofother factors known to effect drug delivery, absorption,pharmacokinetics, including half-life, and efficacy. An effective doseor multi-dose treatment regimen for the compounds of the invention willordinarily be selected to approximate a minimal dosing regimen that isnecessary and sufficient to substantially prevent or alleviate one ormore symptom(s) of a neurological or psychiatric condition in thesubject, as described herein. Thus, following administration of acompound of the present invention, test subjects will exhibit a 10%,20%, 30%, 50% or greater reduction, up to a 75-90%, or 95% or greater,reduction, in one or more symptoms associated with a targeted CNSdisorder, including any targeted neuropsychiatric disorder, such asdepression, compared to placebo-treated or other suitable controlsubjects.

Within additional aspects of the invention, combinatorial formulationsand coordinate administration methods are provided which employ aneffective amount of a compound of the present invention—yielding aneffective formulation or method to alleviate or prevent one or moresymptom(s) of a CNS disorder in a mammalian subject.

Pharmaceutical dosage forms of a compound of the present invention mayoptionally include excipients recognized in the art of pharmaceuticalcompounding as being suitable for the preparation of dosage units asdiscussed above. Such excipients include, without intended limitation,binders, fillers, lubricants, emulsifiers, suspending agents,sweeteners, flavorings, preservatives, buffers, wetting agents,disintegrants, effervescent agents and other conventional excipients andadditives.

The compositions of the invention for treating CNS disorders, includingdepression, can thus include any one or combination of the following: apharmaceutically acceptable carrier or excipient; other medicinalagent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives;diluents; and various other pharmaceutical additives and agents known tothose skilled in the art. These additional formulation additives andagents will often be biologically inactive and can be administered topatients without causing deleterious side effects or interactions withthe active agent.

If desired, a compound of the present invention can be administered in acontrolled release form by use of a slow release carrier, such as ahydrophilic, slow release polymer. Exemplary controlled release agentsin this context include, but are not limited to, hydroxypropyl methylcellulose, having a viscosity in the range of about 100 cps to about100,000 cps.

A compound of the present invention will often be formulated andadministered in an oral dosage form, optionally in combination with acarrier or other additive(s). Suitable carriers common to pharmaceuticalformulation technology include, but are not limited to, microcrystallinecellulose, lactose, sucrose, fructose, glucose dextrose, or othersugars, di-basic calcium phosphate, calcium sulfate, cellulose,methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol,maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch,dextrin, maltodextrin or other polysaccharides, inositol, or mixturesthereof. Exemplary unit oral dosage forms for use in this inventioninclude tablets, which may be prepared by any conventional method ofpreparing pharmaceutical oral unit dosage forms can be utilized inpreparing oral unit dosage forms. Oral unit dosage forms, such astablets, may contain one or more conventional additional formulationingredients, including, but are not limited to, release modifyingagents, glidants, compression aides, disintegrants, lubricants, binders,flavors, flavor enhancers, sweeteners and/or preservatives. Suitablelubricants include stearic acid, magnesium stearate, talc, calciumstearate, hydrogenated vegetable oils, sodium benzoate, leucinecarbowax, magnesium lauryl sulfate, colloidal silicon dioxide andglyceryl monostearate. Suitable glidants include colloidal silica, fumedsilicon dioxide, silica, talc, fumed silica, gypsum and glycerylmonostearate. Substances which may be used for coating includehydroxypropyl cellulose, titanium oxide, talc, sweeteners and colorants.The aforementioned effervescent agents and disintegrants are useful inthe formulation of rapidly disintegrating tablets known to those skilledin the art. These typically disintegrate in the mouth in less than oneminute, and preferably in less than thirty seconds. By effervescentagent is meant a couple, typically an organic acid and a carbonate orbicarbonate. Such rapidly acting dosage forms would be useful, forexample, in the prevention or treatment of acute attacks of panicdisorder.

The compounds and compositions of the invention can be prepared andadministered in any of a variety of inhalation or nasal delivery formsknown in the art. Devices capable of depositing aerosolized formulationsof a compound of the present invention in the sinus cavity or pulmonaryalveoli of a patient include metered dose inhalers, nebulizers, drypowder generators, sprayers, and the like. Pulmonary delivery to thelungs for rapid transit across the alveolar epithelium into the bloodstream may be particularly useful in treating impending episodes ofseizures or panic disorder. Methods and compositions suitable forpulmonary delivery of drugs for systemic effect are well known in theart. Suitable formulations, wherein the carrier is a liquid, foradministration, as for example, a nasal spray or as nasal drops, mayinclude aqueous or oily solutions of a compound of the presentinvention, and any additional active or inactive ingredient(s).

Intranasal delivery permits the passage of active compounds of theinvention into the blood stream directly after administering aneffective amount of the compound to the nose, without requiring theproduct to be deposited in the lung. In addition, intranasal deliverycan achieve direct, or enhanced, delivery of the active compound to theCNS. In these and other embodiments, intranasal administration of thecompounds of the invention may be advantageous for treating a variety ofCNS disorders, including depression, by providing for rapid absorptionand CNS delivery.

For intranasal and pulmonary administration, a liquid aerosolformulation will often contain an active compound of the inventioncombined with a dispersing agent and/or a physiologically acceptablediluent. Alternative, dry powder aerosol formulations may contain afinely divided solid form of the subject compound and a dispersing agentallowing for the ready dispersal of the dry powder particles. Witheither liquid or dry powder aerosol formulations, the formulation mustbe aerosolized into small, liquid or solid particles in order to ensurethat the aerosolized dose reaches the mucous membranes of the nasalpassages or the lung. The term “aerosol particle” is used herein todescribe a liquid or solid particle suitable of a sufficiently smallparticle diameter, e.g., in a range of from about 2-5 microns, for nasalor pulmonary distribution to targeted mucous or alveolar membranes.Other considerations include the construction of the delivery device,additional components in the formulation, and particle characteristics.These aspects of nasal or pulmonary administration of drugs are wellknown in the art, and manipulation of formulations, aerosolizationmeans, and construction of delivery devices, is within the level ofordinary skill in the art.

Yet additional compositions and methods of the invention are providedfor topical administration of a compound of the present invention fortreating CNS disorders, including depression. Topical compositions maycomprise a compound of the present invention and any other active orinactive component(s) incorporated in a dermatological or mucosalacceptable carrier, including in the form of aerosol sprays, powders,dermal patches, sticks, granules, creams, pastes, gels, lotions, syrups,ointments, impregnated sponges, cotton applicators, or as a solution orsuspension in an aqueous liquid, non-aqueous liquid, oil-in-wateremulsion, or water-in-oil liquid emulsion. These topical compositionsmay comprise a compound of the present invention dissolved or dispersedin a portion of a water or other solvent or liquid to be incorporated inthe topical composition or delivery device. It can be readilyappreciated that the transdermal route of administration may be enhancedby the use of a dermal penetration enhancer known to those skilled inthe art. Formulations suitable for such dosage forms incorporateexcipients commonly utilized therein, particularly means, e.g. structureor matrix, for sustaining the absorption of the drug over an extendedperiod of time, for example 24 hours. A once-daily transdermal patch isparticularly useful for a patient suffering from generalized anxietydisorder.

Yet additional formulations of a compound of the present invention areprovided for parenteral administration, including aqueous andnon-aqueous sterile injection solutions which may optionally containanti-oxidants, buffers, bacteriostats and/or solutes which render theformulation isotonic with the blood of the mammalian subject; aqueousand non-aqueous sterile suspensions which may include suspending agentsand/or thickening agents; dispersions; and emulsions. The formulationsmay be presented in unit-dose or multi-dose containers. Pharmaceuticallyacceptable formulations and ingredients will typically be sterile orreadily sterilizable, biologically inert, and easily administered.Parenteral preparations typically contain buffering agents andpreservatives, and may be lyophilized for reconstitution at the time ofadministration.

Parental formulations may also include polymers for extended releasefollowing parenteral administration. Such polymeric materials are wellknown to those of ordinary skill in the pharmaceutical compounding arts.Extemporaneous injection solutions, emulsions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit, daily sub-dose, as described hereinabove, or an appropriate fraction thereof, of the active ingredient(s).

In more detailed embodiments, a compound of the present invention may beencapsulated for delivery in microcapsules, microparticles, ormicrospheres, prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macro emulsions.

The invention also provides pharmaceutical packs or kits comprising oneor more containers holding a compound of the present invention, or anycomposition comprising a compound of the present invention as describedherein, including pharmaceutically acceptable salts and other forms of acompound of the present invention, in a pharmaceutically acceptable,stable form. Optionally packaged with these packs and kits can be anotice, e.g., in a form prescribed by a governmental agency regulatingpharmaceuticals or biological products, reflecting approval by theagency of the manufacture, use and/or sale of the product contained inthe pack or kit for human administration (optionally specifying one ormore approved treatment indications as described herein).

The following examples illustrate certain embodiments of the presentinvention, and are not to be construed as limiting the presentdisclosure.

EXAMPLE I Synthetic Methods for Preparing Substituted1-aryl-3-azabicyclo[3.1.0]hexanes

Although many of the novel 1-aryl-3-azabicyclo[3.1.0]hexanes of theinvention may be prepared according to methods known to those skilled inthe art, they may also be generated, for example, according to theexemplary reaction schemes set forth below. While these novel schemesemploy various intermediates and starting materials, it is to beunderstood that the illustrated processes are also applicable tocompounds having alternative structure, substituent patterns, orstereochemistry depicted in these schemes.

With regard to the following synthetic schemes, and as otherwise usedherein unless specified differently, Ar is a phenyl group substitutedwith two substituents independently selected from halogen, C₁₋₃ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl,C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, anddi(C₁₋₃)alkylamino, an unsubstituted napthyl group or a napthyl grouphaving 1-4 substituents independently selected from halogen, C₁₋₃ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅cycloalkyl, C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl,C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, anddi(C₁₋₃)alkylamino, and R and R₁ are selected from, for example,hydrogen, C₁₋₆ alkyl, halo(C₁₋₆)alkyl, C₃₋₉ cycloalkyl, C₁₋₅alkoxy(C₁₋₆)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, carbamate,halo(C₁₋₃)alkoxy(C₁₋₆)alkyl, C₁₋₃ alkylamino(C₁₋₆)alkyl, anddi(C₁₋₃)alkylamino(C₁₋₆)alkyl, cyano(C₁₋₆)alkyl, methyl, ethyl,trifluoromethyl, trifluoroethyl and 2-methoxyethyl.

Reaction Scheme 1 below generally sets forth an exemplary process forpreparing 1-aryl-3-azabicyclo[3.1.0]hexane analogs from thecorresponding 2-bromo-2-arylacetate or 2-chloro-2-arylacetate. The bromoor chloro acetate react with acrylonitrile to provide the methyl2-cyano-1-arylcyclopropanecarboxylate, which is then reduced to theamino alcohol by reducing agents such as lithium aluminum hydride (LAH)or sodium aluminum hydride (SAH) or NaBH₄ with ZnCl₂. Cyclization of theamino alcohol with SOCl₂ or POCl₃ will provide the1-aryl-3-azabicyclo[3.1.0]hexane. The cyclization of substituted4-aminobutan-1-ol by SOCl₂ or POCl₃ into the pyrrolidine ring system wasreported by Armarego et al., J. Chem. Soc. [Section C: Organic]19:3222-9, (1971), and in Szalecki et al., patent publication PL 120095B2, CAN 99:158251. Oxalyl chloride, phosphorous tribromide,triphenylphosphorous dibromide and oxalyl bromide may be used for thesame purpose. The methyl 2-bromo-2-arylacetate or methyl2-chloro-2-arylacetate may be synthesized from subsitutedbenzoylaldehyde or methyl-2-arylacetate as shown in Reaction Scheme 1A.

Reagents: (a) NaOMe; (b) LiAlH₄; (c) SOCl₂; (d) POCl₃; (e) NaOH orNH₃H₂O

Reagents: (a) CHCl₃, NaOH; (b) SOCl₂; (c) MeOH; (d) NaBrO₃, NaHSO₃

Reaction Scheme 2 below illustrates another exemplary process fortransforming methyl 2-cyano-1-arylcyclopropanecarboxylate to a desiredcompound or intermediate of the invention. Hydrolysis of the cyano esterprovides the potassium salt which can then be converted into the cyanoacid. Reduction and cyclization of the2-cyano-1-arylcyclopropanecarboxylic acid with LAH or LiAlH(OMe)₃according to the procedure outlined in Tetrahedron 45:3683 (1989), willgenerate 1-aryl-3-azabicyclo[3.1.0]hexane. In addition, thecyano-1-arylcyclopropanecarboxylic acid can be hydrogenated and cyclizedinto an amide, which is then reduced to1-aryl-3-azabicyclo[3.1.0]hexane.

Reagents: (a) NaOMe; (b) KOH; (c) HCl; (d) LiAlH(OMe)₃, or LAH, or SAH,then HCl; (e) H₂/Pd or H₂/Ni

Reaction Scheme 3 below discloses an alternative exemplary process forconverting the methyl 2-cyano-1-arylcyclopropanecarboxylate to a desiredcompound or intermediate of the invention. The methyl2-cyano-1-arylcyclopropanecarboxylate is reduced and cyclized into1-aryl-3-aza-bicyclo[3.1.0]hexan-2-one, which is then reduced to1-aryl-3-azabicyclo[3.1.0]hexane [Marazzo, A. et al., Arkivoc 5:156-169,(2004)].

Reagents: (a) H₂/Pd or H₂/Ni; (b) B₂H₆ or BH₃ or LAH, then HCl

Reaction Scheme 4 below provides another exemplary process to prepare1-aryl-3-azabicyclo[3.1.0]hexane analogs. Reaction of 2-arylacetonitrilewith (±)-epichlorohydrin gives approximately a 65% yield of2-(hydroxymethyl)-1-arylcyclopropanecarbonitrile (85% cis) with thetrans isomer as one of the by-products [Cabadio et al., Fr. BollettinoChimico Farmaceutico 117:331-42 (1978); Mouzin et al., Synthesis4:304-305 (1978)]. The methyl 2-cyano-1-arylcyclopropanecarboxylate canthen be reduced into the amino alcohol by a reducing agent such as LAH,SAH or NaBH₄ with ZnCl₂ or by catalytic hydrogenation. Cyclization ofthe amino alcohol with SOCl₂ or POCl₃ provides the1-aryl-3-azabicyclo[3.1.0]hexane. The cyclization of substituted4-aminobutan-1-ol by SOCl₂ or POCl₃ into the pyrrolidine ring system hasbeen reported previously [Armarego et al., J. Chem. Soc. [Section C:Organic] 19:3222-9 (1971); patent publication PL 120095 B2, CAN99:158251).

Reaction Scheme 5 provides an exemplary process for synthesizing the(1R,5S)-(+)-1-aryl-3-azabicyclo[3.1.0]hexanes. Using(S)-(+)-epichlorohydrin as a starting material in the same processdescribed in Scheme 4 will ensure a final product with 1-R chirality[Cabadio, S. et al., Fr. Bollettino Chimico Farmaceutico 117:331-42(1978)].

Reaction Scheme 6 provides an exemplary process to prepare the(1S,5R)-(−)-1-aryl-3S-azabicyclo[3.1.0]hexanes. Using(R)-(−)-epichlorohydrin as a starting material in the same processdescribed in Scheme 4 will ensure a final product with 1-S chirality[Cabadio, S. et al., Fr. Bollettino Chimico Farmaceutico 117:331-42(1978)].

Reaction Scheme 7 provides an alternative exemplary process fortransforming the 2-(hydroxymethyl)-1-arylcyclopropanecarbonitrile to adesired compound or intermediate of the invention via an oxidation andcyclization reaction. Utilizing chiral starting materials(+)-epichlorohydrin or (−)-epichlorohydrin will lead to thecorresponding (+)- or (−)-enantiomers and corresponding chiral analogsthrough the same reaction sequences.

Reaction Scheme 8 provides an exemplary process for transforming theepichlorohydrin to a desired compound or intermediate of the inventionvia a replacement and cyclization reaction. The reaction of methyl2-arylacetate with epichlorohydrin gives methyl2-(hydroxymethyl)-1-arylcyclopropanecarboxylate with the desired cisisomer as the major product. The alcohol is converted into an OR₃ groupsuch as —O-mesylate, —O-tosylate, —O-nosylate, —O-brosylate,—O-trifluoromethanesulfonate. Then OR₃ is replaced by a primary amineNH₂R₄, where R₄ is a nitrogen protection group such as a3,4-dimethoxy-benzyl group or other known protection group. Nitrogenprotecting groups are well known to those skilled in the art, see forexample, “Nitrogen Protecting Groups in Organic Synthesis”, John Wileyand Sons, New York, N.Y., 1981, Chapter 7; “Nitrogen Protecting Groupsin Organic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2; T.W. Green and P. G. M. Wuts in “Protective Groups in Organic Chemistry”,3rd edition, John Wiley & Sons, Inc. New York, N.Y., 1999. When thenitrogen protecting group is no longer needed, it may be removed bymethods well known in the art. This replacement reaction is followed bya cyclization reaction which provides the amide, which is then reducedinto an amine by a reducing agent such as LAH. Finally the protectiongroup is removed to yield the 1-aryl-3-azabicyclo[3.1.0]hexane analogs.Utilizing chiral (S)-(+)-epichlorohydrin as a starting material leads tothe (1R,5S)-(+)-1-aryl-3-azabicyclo[3.1.0]hexane analogs with the samereaction sequence. Similarly, the (R)-(−)-epichlorohydrin will lead tothe (1S,5R)-(−)-1-aryl-3-azabicyclo[3.1.0]hexane analogs.

Reaction Scheme 9 provides an exemplary process for transforming thediol to a desired compound or intermediate of the invention. Reductionof the diester provides the diol which is then converted into an OR₃group such as —O-mesylate, —O-tosylate, —O-nosylate, —O-brosylate,—O-trifluoromethanesulfonate. Then OR₃ is replaced by a primary amineNH₂R₆, where R₆ is a nitrogen protection group such as a3,4-dimethoxy-benzyl group or other protection groups known in the art(e.g., allyl amine, tert-butyl amine). When the nitrogen protectinggroup is no longer needed, it may be removed by methods known to thoseskilled in the art.

-   -   Reagents: (a) NaOMe; (b) NaBH₄; (c) MsCl; (d) NH₃, then HCl; (e)        R₆NH₂; (f) H₂/Pd or acid deprotection, then HCl

Reaction Scheme 10 provides an exemplary process for resolving theracemic 1-aryl-3-aza-bicyclo[3.1.0]hexane to enantiomers. The resolutionof amines through tartaric salts is generally known to those skilled inthe art. For example, using O,O-Dibenzoyl-2R,3R-Tartaric Acid (made byacylating L(+)-tartaric acid with benzoyl chloride) indichloroethane/methanol/water, racemic methamphetamine can be resolvedin 80-95% yield, with an optical purity of 85-98% [SyntheticCommunications 29:4315-4319 (1999)].

Reagents: (a) L-(−)-DBTA; (b) NaOH, then HCl in IPA; (c) D-(+)-DBTA

Reaction Scheme 11 provides an exemplary process for the preparation of3-alkyl-1-aryl-3-azabicyclo[3.1.0]hexane analogs. These alkylation orreductive amination reaction reagents and conditions are generally wellknown to those skilled in the art.

R=Me, Et, Propyl, i-propyl, cyclopropyl, i-butyl, etc.

Enantiomers of compounds within the present invention can be prepared asshown in Reaction Scheme 12 by separation through a chiralchromatography.

Alternatively, enantiomers of the compounds of the present invention canbe prepared as shown in Reaction Scheme 13 using alkylation reactionconditions exemplified in scheme 11.

Reaction Scheme 14 provides an exemplary process for preparing someN-methyl 1-aryl-3-aza-bicyclo[3.1.0]hexane analogs. The commonintermediate N-methyl bromomaleide is synthesized in one batch followedby Suzuki couplings with the various substituted aryl boronic acids.Cyclopropanations are then carried out to produce the imides, which arethen reduced by borane to provide the desired compounds.

-   -   Reagents and conditions: (a) MeNH₂, THF, 10° C., 1.5 hr; (b)        NaOAc, Ac₂O, 60° C., 2 hr; (c) PdCl₂(dppf), CsF, dioxane, 40°        C., 1-6 hr; (d) Me₃SOCl, NaH, THF, 50-65° C., 2-6 hr; (e) 1M        BH₃/THF, 0° C.; 60° C. 2 hr (f) HCl, Et₂O

Reaction Scheme 15 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 16 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 17 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 18 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes. Utilizing chiral starting materials(+)-epichlorohydrin or (−)-epichlorohydrin will lead to thecorresponding chiral analogs through the same reaction sequences.

Reaction Scheme 19 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 20 provides an additional methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes;

Reaction Scheme 21 provides an additional methodology for producing 3-and/or 4-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 22 provides an additional methodology for producing 3-and/or 4-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 23 provides an additional methodology for producing 3-and/or 2-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 24 provides an additional methodology for producing 2-and/or 3-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 25 provides an additional generic methodology forproducing 1-aryl-3-azabicyclo[3.1.0]hexanes.

Reaction Scheme 26 provides another generic methodology for producing1-aryl-3-azabicyclo[3.1.0]hexanes.

EXAMPLE II Preparation ofaza-substituted-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexanehydrochloride compounds and enantiomers thereof

To a stirred solution of1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (30.0 g,132 mmol) in 37% aqueous formaldehyde (25.8 mL) was added formic acid(32.4 mL). The resulting solution was stirred at 90° C. for 6 h. Thereaction was then diluted with water (100 mL) and 2N aqueous sodiumhydroxide added until the pH was greater than 9. The resulting mixturewas extracted with CH₂Cl₂ (2×200 mL) and the combined organic extractswere washed with brine (200 mL), dried (MgSO₄) and concentrated undervacuum to provide the title compound (25.0 g, 79% yield) as an orangeoil: LC (ELS)/MS: >99%, m/z 242.1 [C₁₂H₁₃Cl₂N+H]⁺; ¹H NMR (300 MHz,CDCl₃): δ 0.94 (dd, 1H, J=5.3 Hz, J=7.9 Hz), 1.73 (t, 1H, J=4.7 Hz),1.80 (m, 1H), 2.55 (s, 3H), 2.78 (d, 2H, J=9.2 Hz), 3.35 (d, 1H, J=9.6Hz), 3.54 (d, 1H, J=9.3 Hz), 6.99 (dd, 1H, J=2.1 Hz, J=8.3 Hz), 7.24 (d,1H, J=2.1 Hz), 7.35 (d, 1H, J=8.3 Hz).

A stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexanehydrochloride (19.3 g, 72.9 mmol) in CH₂Cl₂ (100 mL) was rendered basicwith 2N NaOH (100 mL). The resulting mixture was extracted with CH₂Cl₂(2×100 mL) and the combined extracts dried, filtered and concentratedunder reduced pressure. The residue was dissolved in acetonitrile (200mL) and bromoethane (15.9 g, 146 mmol) added at room temperature. Themixture was stirred for 4 h during which time a white precipitateformed. After this time the reaction was concentrated under reducedpressure then treated with 2N NaOH (200 mL). Subsequent extraction withCH₂Cl₂ (3×100 mL) drying the combined extracts (MgSO₄), filtration andconcentration under reduced pressure afforded a crude residue. Thisresidue was purified by passing through a silica gel plug, eluting withether, to yield the title compound (12.4 g, 66%) as a clear, viscousoil. This material was then used directly for either chiral separationor hydrochloride salt formation as provided in Example II, Section Dhereinbelow.

To a stirred solution of1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (10.0 g,43.8 mmol) in DMF (20 mL) was added 2-iodoethane (9.67 g, 56.9 mmol) andDIPEA (7.35 g, 56.9 mmol). The resulting solution was stirred at ambienttemperature for 6 h. After this time, the solvent was removed undervacuum and the residue was dissolved in CH₂Cl₂ (50 mL). The organiclayer was washed with water (2×50 mL), 2N sodium hydroxide (50 mL) andbrine (50 mL). The organics were dried (Na₂SO₄) and concentrated undervacuum. Three reactions were run in parallel and then combined forpurification via column chromatography (silica gel, EtOAc) to providethe title compound (17.3 g, 49% yield) as a yellow oil: LC (ELS)/MS:91%, m/z 271.6 [C₁₄H₁₇Cl₂N+H]⁺; ¹H NMR (300 MHz, CDCl₃): δ 0.75 (dd, 1H,J=4.2 Hz, J=8.1 Hz), 1.05 (dd, 6H, J=4.7 Hz, J=6.3 Hz), 1.44 (t, 1H,J=4.2 Hz), 1.67 (td, 1H, J=3.9 Hz, J=8.0 Hz), 2.50 (m, 3H), 3.11 (d, 1H,J=8.6 Hz), 3.31 (d, 1H, J=8.4 Hz), 6.96 (dd, 1H, J=2.1 Hz, J=8.3 Hz),7.22 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J=8.3 Hz).

D. Chiral Separation Conditions and Hydrochloride Salt Formation

The 3 racemic mixtures synthesized above in Sections A, B and C of thisExample II were subjected to chiral chromatography using the followingconditions:

1: Chiralcel OD column, 4.6 mm×250 mm; 99:1 heptanes/i-propanol with0.1% DEA added; 100 mL/min; 275 nm; 50 mg/mL loading. Peak A eluted at13 minutes and peak B eluted at 14.5 minutes.

2: Chiralcel OD column, 4.6 mm×250 mm; 90:10 heptanes/ethanol with 0.1%TFA added; 100 mL/min; 275 nm; 50 mg/mL loading. Peak A eluted at 9minutes and peak B eluted at 27 minutes.

3: Chiralcel OD column, 4.6 mm×250 mm; 93:7 heptanes/ethanol with 0.1%TFA added; 100 mL/min; 275 nm; 50 mg/mL loading. Peak A eluted at 12minutes and peak B eluted at 19 minutes.

The appropriate fractions were collected and concentrated under reducedpressure. The resulting residue was dissolved in CH₂Cl₂, washed with 2Nsodium hydroxide, dried (Na₂SO₄) and the solvent removed under vacuum toyield the corresponding freebase.

To a stirred solution of the appropriate freebase in CH₂Cl₂ (1 g/mL) wasadded 2 M HCl in ether (2 eq.). The mixture was stirred at ambienttemperature for 16 h. The solvent was then removed under reducedpressure and the resulting salt was slurried in ether and collected on aglass frit. Subsequent washing with ether and drying under vacuumprovided the desired hydrochloride salt set forth below.

7.72 g (88%), white solid: LC (ELS)/MS: 98.8%, m/z 242 [C₁₂H₁₃Cl₂N]+; ¹HNMR (300 MHz, CDCl₃): δ 1.21 (t, 1H, J=7.8 Hz), 2.04 (td, 1H, J=4.3 Hz,J=8.6 Hz), 2.32 (dd, 1H, J=4.8 Hz, J=6.9 Hz), 2.92 (d, 3H, J=4.5 Hz),3.30 (m, 2H), 3.94 (dd, 1H, J=5.1 Hz, J=11.0 Hz), 4.11 (dd, 1H, J=5.2Hz, J=10.9 Hz), 7.03 (dd, 1H, J=2.2 Hz, J=8.3 Hz), 7.29 (d, 1H, J=2.2Hz), 7.42 (d, 1H, J=8.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 136.1, 131.6,130.3, 129.6, 127.6, 124.5, 58.5, 55.2, 39.3, 28.5, 22.0, 14.5; [α]²⁵_(D) −65.8° (c 1.00, methanol); Anal. Calcd. for C₁₂H₁₄Cl₃N: C, 51.73;H, 5.06; N, 5.03. Found: C, 51.68; H, 5.14; N, 4.92.

7.74 g (88%), white solid: LC (ELS)/MS: 99.3%, m/z 242 [C₁₂H₁₃Cl₂N]⁺; ¹HNMR (300 MHz, CDCl₃): δ 1.21 (t, 1H, J=7.8 Hz), 2.04 (td, 1H, J=4.3 Hz,J=8.6 Hz), 2.33 (m, 1H), 2.91 (m, 3H), 3.27 (m, 2H), 3.94 (dd, 1H, J=5.2Hz, J=11.0 Hz), 4.12 (dd, 1H, J=5.2 Hz, J=10.9 Hz), 7.02 (dd, 1H, J=2.2Hz, J=8.3 Hz), 7.27 (m, 1H), 7.42 (d, 1H, J=8.3 Hz); ¹³C NMR (75 MHz,CDCl₃): δ 138.6, 133.4, 132.2, 131.4, 129.6, 127.0, 60.3, 57.4, 41.6,31.1, 23.9, 16.7; [α]²⁵ _(D) +67.0° (c 1.00, methanol); Anal. Calcd. forC₁₂H₁₄Cl₃N: C, 51.73; H, 5.06; N, 5.03. Found: C, 51.78; H, 4.96; N,4.97.

2.31 g (45%), white solid: LC (ELS)/MS: >99%, m/z 256 [C₁₃H₁₅Cl₂N+H]⁺;¹H NMR (300 MHz, CDCl₃): δ 1.19 (t, 1H, J=7.7 Hz), 1.52 (t, 3H, J=7.1Hz), 2.03 (td, 1H, J=4.1 Hz, J=8.3 Hz), 2.39 (dd, 1H, J=4.7 Hz, J=6.7Hz), 3.23 (m, 4H), 3.93 (dd, 1H, J=5.2 Hz, J=10.8 Hz), 4.12 (dd, 1H,J=5.3 Hz, J=10.8 Hz), 7.02 (dd, 1H, J=2.0 Hz, J=8.3 Hz), 7.27 (m, 1H),7.42 (d, 1H, J=8.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 136.8, 131.3, 130.1,129.6, 127.7, 125.0, 56.4, 53.4, 49.9, 28.7, 21.5, 15.0, 9.4; [α]²⁵ _(D)−62.7° (c 1.096, methanol); Anal. Calcd. for C₁₃H₁₆Cl₃N: C, 53.36; H,5.51; N, 4.79. Found: C, 52.78; H, 5.24; N, 4.71.

3.64 g (56%), white solid: LC (ELS)/MS: 97%, m/z 256 [C₁₃H₁₅Cl₂N+H]⁺; ¹HNMR (300 MHz, CDCl₃): δ 1.18 (t, 1H, J=7.3 Hz), 1.52 (t, 3H, J=7.2 Hz),2.02 (m, 1H), 2.38 (m, 1H), 3.21 (m, 4H), 3.92 (d, 1H, J=10.9 Hz), 4.11(d, 1H, J=10.8 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.27 (m, 1H), 7.42 (d, 1H,J=8.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 137.5, 131.7, 130.1, 129.8, 128.2,125.6, 57.2, 54.0, 50.5, 29.4, 22.2, 15.8, 9.8; [α]²⁵ _(D) +69.2° (c1.1, methanol); Anal. Calcd. for C₁₃H₁₆Cl₃N: C, 53.36; H, 5.51; N, 4.79.Found: C, 52.71; H, 5.23; N, 4.65.

5.61 g, white solid: LC (ELS)/MS: >99%, m/z 270 [C₁₄H₁₇Cl₂N+H]⁺; ¹H NMR(300 MHz, CDCl₃): δ 1.15 (t, 1H, J=7.7 Hz), 1.55 (d, 6H, J=6.5 Hz), 2.02(td, 1H, J=4.4 Hz, J=8.7 Hz), 2.50 (dd, 1H, J=4.8 Hz, J=6.7 Hz), 3.28(m, 3H), 3.89 (dd, 1H, J=5.5 Hz, J=11.0 Hz), 4.08 (dd, 1H, J=5.5 Hz,J=10.9 Hz), 7.03 (dd, 1H, J=2.2 Hz, J=8.3 Hz), 7.27 (d, 1H, J=3.0 Hz),7.42 (d, 1H, J=8.3 Hz); ¹³C NMR (75 MHz, CDCl₃): δ 136.9, 131.7, 130.1,129.6, 127.7, 125.3, 58.6, 55.1, 52.2, 28.8, 21.7, 17.1, 14.9; [α]²⁵_(D) −74.1° (c 1.00, methanol); Anal. Calcd. for C₁₄H₁₈Cl₃N: C, 54.83;H, 5.92; N, 4.57. Found: C, 54.50; H, 5.85; N, 4.42.

5.20 g, white solid: LC (ELS)/MS: >99%, m/z 270 [C₁₄H₁₇Cl₂N+H]⁺; ¹H NMR(300 MHz, CDCl₃): δ 1.15 (t, 1H, J=7.7 Hz), 1.55 (d, 6H, J=6.5 Hz), 2.01(td, 1H, J=4.4 Hz, J=8.7 Hz), 2.50 (dd, 1H, J=4.8 Hz, J=6.7 Hz), 3.26(ddd, 1H, J=7.0 Hz, J=14.6 Hz, J=28.8 Hz), 3.90 (dd, 1H, J=5.5 Hz,J=11.0 Hz), 4.08 (dd, 1H, J=5.5 Hz, J=10.9 Hz), 7.02 (dd, 1H, J=2.2 Hz,J=8.3 Hz), 7.27 (d, 1H, J=2.4 Hz), 7.42 (d, 1H, J=8.3 Hz); ¹³C NMR (75MHz, CDCl₃): δ 137.0, 131.2, 129.9, 128.5, 127.3, 124.0, 58.0, 55.0,50.7, 29.1, 20.9, 17.4, 14.2; [α]²⁵ _(D) +76.8° (c 1.00, methanol);Anal. Calcd. For C₁₄H₁₈Cl₃N: C, 54.83; H, 5.92; N, 4.57. Found: C,54.69; H, 5.82; N, 4.44.

To a 3-necked flask under nitrogen was added1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (30 g) andanhydrous DMF (220 mL). The mixture was then cooled to between 0 and 10°C. using an ice/salt/water bath. At this point sodium hydride (4.68 g)was added portionwise over approximately 1 h. Significant gas evolutionwas noted on addition of the sodium hydride. On completion of theaddition the reaction was allowed to stir for 30 mins at roomtemperature before the addition of bromopropane (17 mL). The reactionwas then allowed to stir overnight at room temperature. TLC of thereaction mixture revealed no starting material. The reaction wasquenched by adding the reaction mixture dropwise to cold water (<10°C.). This led to the formation of a slurry; the solid was dissolved onaddition of ethyl acetate (500 mL). The organics were separated andaqueous re-extracted with ethyl acetate (1 L). The organics were againseparated and washed with water (2×500 mL) and brine (2×500 mL), leadingto the formation of an emulsion. The emulsion was separated after theaddition of more water (500 mL) and ethyl acetate (500 mL). The organicswere then separated, dried over magnesium sulphate, filtered andconcentrated in vacuo to give a brown oil (36.8 g). A sample was sentfor ¹H NMR (GMCP408A) and this showed the crude product (36.8 g, 94%yield, purity >90%). This was used directly in the reduction stage.

To a 3-necked flask under nitrogen was added the imide (36.8 g) in THF(300 mL). The mixture was cooled to 0° C. and 1M BH₃ in THF was addeddropwise. On completion of the addition the reaction was heated toreflux for 4 h. TLC of the reaction mixture showed that no startingmaterial remained. The reaction mixture was cooled to 0° C. and quenchedwith 6N HCl (470 mL). The quenched mixture was then concentrated invacuo to a volume of approximately 300 mL. The mixture was again cooledto 0° C. and made basic with 750 mL of 5M NaOH solution. The mixture wasthen extracted with DCM (2×1 L). The organics were then dried, filteredand concentrated in vacuo. The material was subjected to columnchromatography (98% DCM: 2% methanol: 0.1% ammonia). However this led tothe isolation of only mixed fractions. An alternative solvent systemusing 20% ethyl acetate: 80% hexane was employed. Three sets offractions were obtained. Samples of each set of fractions were analysedvia ¹H NMR and showed that two sets of fractions (designated A and C)contained mostly product with small amounts of impurities present. Thethird set of fractions (designated B) was shown to contain only a smallamount of product with significant other impurities present. The A and Csets of fractions were combined (7.7 g) and dissolved in diethyl ether(8 mL) before being cooled to 0° C. At this point 1M HCl in ether (143mL) was added carefully to the mixture to form the salt. The slurry wasstirred for 30 mins at 0° C. before being filtered. The salt was thendried in the oven overnight at ambient temperature. This gave theproduct as a white solid (6.08 g, 18.2%). ¹H NMR (300 MHz, d₆-DMSO) δ11.28 (1H, brs, NH⁺), 7.62-7.59 (2H, m, ArH), 7.28-7.25 (1H, m, ArH),3.97-3.90 (1H, m, NCH₂), 3.63-3.44 (3H, m, NCH₂), 3.09-3.01 (2H, m,NCH₂), 2.21-2.16 (1H, m, CH), 1.88 (1H, t, J=5.4 Hz, CH₂), 1.77-1.69(2H, m, CH₂CH₃), 1.11 (1H, obs t, J=7.3 Hz, CH₂), 0.87 (3H, obs t, J=7.3Hz, CH₃); ¹³C NMR (75 MHz, δ-CDCl₃) δ 140.5, 131.1, 130.4, 129.1, 128.9,127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.2, 15.9, 10.8; MS (m/z) 270(MH⁺, 100).

To a stirred solution of(1R,5S)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride(10 g) in anhydrous DMF (70 mL) under nitrogen was added DIPEA (8.48 mL,1.3 eq). The reaction was allowed to stir for 30 mins before theaddition of propyl bromide (6.15 mL). The reaction was stirred at roomtemperature for 2 h. TLC of the reaction revealed a mixture of startingmaterial and product. Therefore the reaction was continued with afurther addition of 0.7 eq of DIPEA, heated to 40° C. and allowed tostir for 4 h. The reaction was then allowed to stand overnight at roomtemperature. TLC of the reaction revealed mainly product with a smallamount of starting material and baseline material present. The reactionmixture was then concentrated in vacuo under reduced pressure to removethe DMF. This gave a liquid, which solidified on standing (pink solid).This was taken up in DCM (150 mL) and washed with water (100 mL). Theorganics were then separated, dried over magnesium sulphate, filteredand concentrated in vacuo. Once again a pink solid was obtained. Thismaterial was purified via column chromatography eluted using 98% DCM: 2%methanol: 0.1% ammonia. This gave pure compound (15.3 g) as a solid (15%DMF present). The solid was slurried in ethyl acetate (150 mL) and mixedwith saturated aqueous NaHCO₃ solution (75 mL). The solid dissolved onaddition of the base. The organics were separated and washed with water(2×200 mL) before drying over magnesium sulphate, filtering andconcentrating in vacuo to give an oil (8.8 g). The oil was taken up indiethyl ether (9 mL) before being cooled to 0° C. At this point 1M HClin ether (163 mL) was added carefully to the mixture to form the salt.The slurry was stirred for 30 mins at 0° C. before being filtered. Thesalt was then dried in the oven overnight at ambient temperature. Thisgave the product as a white solid (7.73 g, 66.7%). ¹H NMR (300 MHz,d₆-DMSO) δ 11.19 (1H, brs, NH⁺), 7.62-7.57 (2H, m, ArH), 7.29-7.25 (1H,m, ArH), 3.95-3.90 (1H, dd, J=11.1, 4.5 Hz, NCH₂), 3.64-3.59 (1H, dd,J=11.1, 4.5 Hz, NCH₂), 3.55-3.41 (2H, m, NCH₂), 3.07-3.04 (2H, m, NCH₂),2.21-2.16 (1H, m, CH), 1.88 (1H, t, J=5.4 Hz, CH₂), 1.77-1.69 (2H, m,CH₂CH₃), 1.11 (1H, obs t, J=7.3 Hz, CH₂), 0.87 (3H, obs t, J=7.3 Hz,CH₃); ¹³C NMR (75 MHz, δ-CDCl₃) δ 140.5, 131.1, 130.4, 129.1, 128.9,127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.2, 15.9, 10.8; MS (m/z) 270(MH⁺, 100).

To a stirred solution of(1S,5R)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride(10 g) in anhydrous DMF (70 mL) under nitrogen was added DIPEA (8.48 mL,1.3 eq). The reaction was allowed to stir for 30 mins before theaddition of propyl bromide (6.15 mL). The reaction was stirred at roomtemperature for 2 h. TLC of the reaction revealed a mixture of startingmaterial and product. Therefore the reaction was continued with afurther addition of 0.7 eq of DIPEA, heated to 40° C. and allowed tostir for 4 h. The reaction was then allowed to stand overnight at roomtemperature. TLC of the reaction revealed mainly product with a smallamount of starting material and baseline material present. The reactionmixture was then concentrated in vacuo under reduced pressure to removethe DMF. This gave a liquid, which solidified on standing (pink solid).This was taken up in DCM (150 mL) and washed with water (100 mL). Theorganics were then separated, dried over magnesium sulphate, filteredand concentrated in vacuo. Once again a pink solid was obtained. Thismaterial was purified via column chromatography eluted using 98% DCM: 2%methanol: 0.1% ammonia. This gave pure compound (15.9 g) as a solid (15%DMF present). The solid was slurried in ethyl acetate (150 mL) and mixedwith saturated aqueous NaHCO₃ solution (75 mL). The solid dissolved onaddition of the base. The organics were separated and washed with water(2×200 mL) before drying over magnesium sulphate, filtering andconcentrating in vacuo to give an oil (8.9 g). The oil was taken up indiethyl ether (9 mL) before being cooled to 0° C. At this point 1M HClin ether (165 mL) was added carefully to the mixture to form the salt.The slurry was stirred for 30 mins at 0° C. before being filtered. Thesalt was then dried in the oven overnight at ambient temperature. Thisgave the product as a white solid (8.61 g, 75%). ¹H NMR (300 MHz,d₆-DMSO) δ 11.20 (1H, brs, NH⁺), 7.62-7.57 (2H, m, ArH), 7.29-7.25 (1H,m, ArH), 3.94-3.90 (1H, dd, J=11.1, 4.5 Hz, NCH₂), 3.64-3.59 (1H, dd,J=11.1, 4.5 Hz, NCH₂), 3.55-3.41 (2H, m, NCH₂), 3.07-3.04 (2H, m, NCH₂),2.21-2.16 (1H, m, CH), 1.89 (1H, obs t, J=5.4 Hz, CH₂), 1.80-1.67 (2H,m, CH₂CH₃), 1.11 (1H, obs t, J=7.3 Hz, CH₂), 0.87 (3H, t, J=7.3 Hz,CH₃); ¹³C NMR (75 MHz, δ-CDCl₃) δ 140.5, 131.1, 130.4, 129.1, 128.9,127.1, 56.5, 55.8, 54.5, 29.3, 23.4, 18.3, 15.9, 10.9; MS (m/z) 270(MH⁺, 100).

To a stirred solution of1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (15.8 g) inDMF (63 ml) was added sodium hydride (60 wt. % in oil; 2.5 g) with thetemperature kept below 20° C. The suspension was then stirred at roomtemperature for 20 mins before 1-bromobutane (9.9 ml) was added. Thesolution was then stirred at room temperature for 24 h when TLC (20%ethyl acetate in hexanes) indicated complete reaction. The solution wasquenched into water (500 ml), extracted with ether (2×250 ml) and theextracts washed with water (2×250 ml), saturated brine (2×250 ml), dried(MgSO₄) and evaporated, yielding 15.6 g (81%) imide.

The imide above (15.6 g) was dissolved in THF (310 ml) and a solution ofborane in THF (1M; 225 ml) was added with the temperature kept below 5°C. The solution was then heated to reflux for 4 h when TLC (20% ethylacetate in hexane) indicated complete reaction. The solution was cooledto 0° C. and quenched by the addition of dilute HCl (6M; 200 ml) withthe temperature kept below 110° C. The solution was then extracted withether (2×200 ml), the aqueous made basic with sodium hydroxide (5M; 480ml), extracted with ether (3×150 ml), the extracts combined, dried(MgSO₄) and evaporated, to give a crude oil with a yield of 3.2 g.

The oil was added to HCl in ether (2M; 20 ml), stored overnight at −20°C. and the resultant solid filtered off and washed with ether (2×10 ml).TLC (20% ethyl acetate in hexanes) indicated two components so the solidwas dissolved in water (50 ml) made basic with solid K₂CO₃ to pH 10 andextracted with ether (3×100 ml). The extracts were dried (MgSO₄) andevaporated. The product was then purified by chromatography [SiO₂ (22.7g): (25% EtOAc in hexanes)] to give the required material as a yellowoil, 0.7 g (5%); ¹HNMR (300 MHz, CDCl₃) δ 7.16-7.06 (m, 4H, ArH), 3.97(t, 1H, J=6.3 Hz, NCH₂), 3.78 (s, 3H, NCH₂), 2.34 (s, 3H, ArCH₃), 1.87(m, 1H, CHCH₂), 1.19 (t, 1H, J=5.5 Hz, CHCH₂), 0.87 (m, 1H, CHCH₂); MS(m/z) 188 (MH⁺, 100).

To a stirred solution of the1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylic acid (28.3 g) inacetyl chloride (142 ml) was heated to reflux for 3 h, cooled to roomtemperature and evaporated. The oil was dissolved in toluene (100 ml)and evaporated to dryness. This was then repeated twice beforetriturating the semi-solid in hexane (100 ml). The solid was filteredoff, washed with hexane and pulled dry under a nitrogen atmosphere togive a brown solid, yield=26.7 g (101%); ¹HNMR (300 MHz, CDCl₃) δ7.52-7.46 (m, 2H, ArH), 7.27-7.24 (m, 1H, ArH), 3.35-3.30 (m, 1H, CH),2.13-2.10 (m, 1H, CH), 1.97-1.95 (m, 1H, CH).

To a stirred solution of the anhydride prepared as described in ExampleVII, Section A above (26.7 g) in THF (365 ml) was added tert-butylamine(23 ml) with the temperature kept below 20° C. The suspension was thenstirred at room temperature for 1 h when TLC (50% ethyl acetate inhexane) indicated complete reaction. The solvent was evaporated off andthe resultant sticky mass used crude in the next reaction.

A stirred suspension of the amide prepared as described in Example VII,Section B above and sodium acetate (4.3 g) in acetic anhydride (145 ml)was heated to reflux for 4 h where TLC (50% ethyl acetate in hexanes)indicated complete reaction so the solvent was evaporated off and theoil absorbed onto silica (49.7 g). The product was then purified bychromatography [SiO₂ (503.7 g): (10% EtOAc in hexanes)] to give therequired material as a yellow oil, in a yield of 23.7 g (73%); ¹HNMR(300 MHz, CDCl₃) δ 7.52-7.46 (m, 2H, ArH), 7.23-7.20 (m, 1H, ArH),2.64-2.60 (m, 1H, CH), 1.72-1.66 (m, 2H, CH), 1.52 (s, 9H, Bu^(t)).

To a stirred solution of the imide prepared as described in Example VII,Section C above (23.7 g) in THF (395 ml) at 5° C. was added a solutionof borane in THF (1M; 304 ml) with the temperature kept below 5° C. Thesolution was then heated to reflux for 2 h when TLC (20% ethyl acetatein hexane) indicated complete reaction. The solution was cooled to 0° C.and quenched by the addition of dilute HCl (6M; 400 ml) with thetemperature kept below 10° C. The THF was evaporated off and the whitesolid filtered off and dried at 45° C. in vacuo overnight, yielding 17.0g (75%) of the desired product. ¹HNMR (300 MHz, CDCl₃) δ 7.71 (d, 1H,J=2.4 Hz, ArH), 7.57 (d, 1H, J=8.4 Hz, ArH), 7.36 (dd, 1H, J=8.4 Hz,J=2.4 Hz, ArH), 4.86 (br s, 2H, CH₂), 3.69-3.63 (m, 1H, CH), 3.46-3.43(m, 1H, CH), 2.37-2.31 (m, 1H, CH), 1.45-1.42 (m, 1H, CH), 1.32 (s, 9H,Bu^(t)); MS (m/z) 299 (MH⁺, 100).

To a stirred solution of the amide prepared as described in Example VII,Section D above (15.1 g) in THF (270 ml) was added a solution of boranein THF (1M; 203 ml) at 20° C. The solution was then heated to reflux for16 h when TLC (20% ethyl acetate in hexane) indicated incompletereaction so the solution was cooled to room temperature and a furtherportion of borane in THF (1M; 130 ml) was added at 20° C. The solutionwas then again heated to reflux and held for 24 h. TLC indicatedapproximately 50% reaction so the solution was cooled to 0° C. andquenched by the addition of dilute HCl (6M; 400 ml) with the temperaturekept below 10° C. The THF was evaporated off, the white solid filteredoff, and the aqueous extracted with ethyl acetate (3×250 ml). Theaqueous was made basic with NaOH (5M; 500 ml) and the product extractedinto ether (3×200 ml), dried (MgSO₄) and evaporated to give a colourlessoil, in a yield of 5.9 g (41%).

The crude amine was added to a solution of maleic acid (2.3 g) inmethanol (11.5 ml) and stored at −20° C. overnight. The solid wasfiltered off, washed with methanol (2.5 ml) and dried at 45° C. in vacuoovernight, yielding the title compound (1.1 g, 5%); ¹HNMR (300 MHz,CDCl₃) δ 7.31-7.19 (m, 2H, ArH), 6.95-6.91 (m, 1H, ArH), 3.28 (d, 1H,J=8.4 Hz, CH), 3.10 (d, 1H, J=8.4 Hz, CH), 2.48-2.40 (m, 4H, CH),1.68-1.62 (m, 1H, CH), 1.47-1.33 (m, 5H, CH), 0.92-0.87 (m, 3H, CH₃),0.77-0.74 (m, 1H, CH); MS (m/z) 284 (M⁺, 100).

Pursuant to steps a and b of Reaction Scheme 14, a solution ofbromomaleic anhydride (52.8 g, 0.298 mol) in diethyl ether (250 mL) wascooled to 5° C. A 2 M solution of methylamine in THF (298 mL, 0.596 mol,2 eq.) was added dropwise over 1 hour and the reaction stirred for afurther 30 minutes, maintaining the temperature below 10° C. Theresulting precipitate was filtered, washed with diethyl ether (2×100 mL)and air-dried for 30 minutes, then suspended in acetic anhydride (368mL) and sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) added. The reactionwas heated to 60° C. for 2 hours and solvent was then removed in vacuo.The residue was taken up in DCM (500 mL) and washed with saturatedsodium bicarbonate solution (2×500 mL) and water (2×300 mL). Organicswere dried over MgSO₄ (89 g), filtered and reduced in vacuo. Theresulting oil was azeotroped with toluene (4×100 mL) to give N-methylbromomaleimide as a beige solid. Yield=41.4 g (73%); ¹H NMR (300 MHz,CDCl₃) δ 6.95 (1H, s, CH), 3.07 (3H, s, NCH₃).

B. General Synthetic Procedure for Preparation of3-Aryl-1-methyl-pyrrole-2,5-diones

Pursuant to step c of Reaction Scheme 14, the following provides ageneral procedure for synthesis of 3-aryl-1-methyl-pyrrole-2,5-diones.N-Methyl bromomaleimide (20 mL of a 0.5 M solution in 1,4-dioxane, 1.96g net, 10 mmol), aryl boronic acid (11 mmol, 1.1 eq.), cesium fluoride(3.4 g, 22 mmol, 2.2 eq.) and[1,1′-bis-(diphenylphosphino)ferrocene]palladium (II) chloride (0.4 g,0.5 mmol, 5 mol %) were stirred at 40° C. for between 1 and 6 hours.Reactions were filtered, solids washed with 1,4-dioxane (5 mL) andsolvents removed in vacuo (two of the solids required an extra wash withdichloromethane at this stage). Residues were taken up in DCM (5 mL)then purified either by passing through a flash silica chromatographycartridge (20 g silica) or by column chromatography (30 g silica, elutedwith 4:1 hexane:ethyl acetate then 2:1 hexane:ethyl acetate). Solventswere removed in vacuo to give the required crude products as solids. Thecompounds shown below (NMR data also listed-below) were prepared usingthe foregoing general procedure:

Yield=1.4 g (61%); ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.81 (1H, m, ArH),7.72-7.68 (1H, m, ArH), 7.29-7.20 (1H, m, ArH), 6.71 (1H, s, CH), 3.07,(3H, s, NCH₃); MS (m/z) 224 [MH⁺].

Yield=1.2 g (53%); ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.59 (2H, m, ArH),7.28-7.21 (1H, obs t, J=8.1 Hz, Arm, 6.69 (1H, s, CH), 3.06 (3H, s,NCH₃), 2.32-2.31 (3H, d, J=2.3 Hz, ArCH₃); MS (m/z) 220 [MH⁺].

Yield=1.4 g (62%); ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.76 (2H, m, ArH),7.12-7.06 (1H, obs t, J=8.9 Hz, ArH), 6.67 (1H, s, CH), 3.08 (3H, s,NCH₃), 2.33 (3H, d, J=1.8 Hz, ArCH₃); MS (m/z) 220 [MH⁺].

Yield=1.8 g (78%); ¹H NMR (300 MHz, CDCl₃) δ 8.39-8.31 (1H, m, ArH),7.02-6.89 (3H, m, 2×ArH, CH), 3.08 (3H, s, NCH₃); MS (m/z) 236 [MH⁺].

Yield=2.0 g (76%); ¹H NMR (300 MHz, CDCl₃) δ 7.70-7.67 (1H, d, J=8.4 Hz,ArH), 7.52 (1H, d, J=1.9 Hz, ArH), 7.37-7.33 (1H, m, ArH), 7.02 (1H, s,CH), 3.09 (3H, s, NCH₃); MS (m/z) 256 [MH⁺].

Yield=1.30 g, (65%); ¹H NMR (300 MHz, CDCl₃) δ 8.62 (br s, 1H), 7.83 (m,1H), 7.76 (m, 2H), 7.18 (m, 1H), 7.12 (m, 1H), 6.75 (s, 1H), 3.94 (s,3H), 3.09 (s, 3H).

Yield=1.02 g, (48%); ¹H NMR (300 MHz, CDCl₃) δ 8.62 (m, 1H), 7.83 (m,1H), 7.75 (m, 2H), 7.18 (m, 1H), 7.11 (m, 1H), 6.76 (s, 1H), 4.17 (q,2H, J=7 Hz), 3.10 (s, 3H), 1.49 (t, 3H, J=7 Hz); MS (M+1) 282.1.

C. General Synthetic Procedure for Preparation of1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane-2,4-diones

Pursuant to step d of Reaction Scheme 14, trimethylsulphoxonium chloride(1.2 eq.) and sodium hydride (60% dispersion in mineral oil, 1.2 eq.)were suspended in THF (50 vol) and heated at reflux (66° C.) for 2hours. The reactions were cooled to 50° C. and a solution of1-methyl-3-(aryl)pyrrole-2,5-dione (1 eq.) in THF (10 mL) was added inone portion. The reactions were heated at 50° C. for between 2 and 4hours and then at 65° C. for a further 2 hours if required (as judged bydisappearance of starting material by TLC), and then cooled to roomtemperature. Reactions were quenched by the addition of IMS (5 mL) andthe solvents removed in vacuo. The residues were taken up in DCM (35 mL)and washed with water (3×35 mL). Combined aqueous washes wereback-extracted with DCM (15 mL), organic portions combined and solventremoved in vacuo. The reactions were purified by column chromatography(30 g silica, eluting with increasingly polar fractions of ethyl acetatein hexane) and solvents removed in vacuo to give the3-methyl-1-(aryl)-3-aza-bicyclo[3.1.0]hexane-2,4-diones as crude solids.The compounds shown below (NMR data also listed below) were preparedusing the foregoing general procedure:

Yield=0.6 g (40%); ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.26 (1H, m, ArH),7.20-7.07 (2H, m, ArH), 2.92 (3H, s, NCH₃), 2.75-2.71 (1H, dd, J=8.1 Hz,3.7 Hz, CH), 1.87-1.85 (1H, obs t, J=4.2 Hz, CH₂), 1.81-1.77 (1H, dd,J=8.1 Hz, 4.8 Hz, CH₂); MS (m/z) 238 [MH⁺].

Yield=0.2 g (16%); ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.14 (1H, t, J=7.8 Hz,ArH), 7.10-7.02 (2H, m, ArH), 2.91 (3H, s, NCH₃), 2.71-2.67 (1H, dd,J=8.1 Hz, 4.0 Hz, CH), 2.25 (3H, d, J=1.9 Hz, ArCH₃), 1.87-1.78 (2H, m,CH₂); MS (m/z) 234 [MH⁺].

Yield=0.5 g (33%); ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.21 (1H, m, ArH),7.19-7.14 (1H, m, ArH), 7.02-6.96 (1H, t, J=9.0 Hz), 2.92 (3H, s, NCH₃),2.69-2.65 (1H, dd, J=7.8 Hz, 4.1 Hz, CH), 2.27-2.26 (3H, d, J=2.2 Hz,ArCH₃), 1.84-1.77 (2H, m, CH₂); MS (m/z) 234 [MH⁺].

Yield=0.7 g (36%); ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.20 (1H, m, ArH),6.94-6.79 (2H, m, ArH), 2.92 (3H, s, NCH₃), 2.65-2.61 (1H, dd, J=7.7 Hz,4.1 Hz, CH), 1.89-1.83 (2H, m, CH₂); MS (m/z) 238 [MH⁺].

Yield=1.0 g (47%); ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.44 (1H, s, ArH),7.29-7.28 (2H, m, ArH), 2.94 (3H, s, NCH₃), 2.62-2.58 (1H, dd, J=7.7 Hz,4.8 Hz, CH), 1.95-1.91 (2H, m, CH₂); MS (m/z) 270 [MH⁺].

Yield=580 mg, (41%)); MS (M+1) 282.1. ¹H NMR (CDCl₃) δ 7.79 (m, 1H),7.69-7.76 (m, 2H), 7.44 (m, 1H), 7.16 (m, 1H), 7.12 (m, 1H), 3.92 (s,3H), 2.96 (s, 3H), 2.78 (m, 1H), 1.87-1.97 (m, 2H).

Yield=360 mg, (39%)); ¹H NMR (CDCl₃) δ 7.78 (m, 1H), 7.71 (m, 2H), 7.43(m, 1H), 7.16 (m, 1H), 7.11 (m, 1H), 4.15 (q, 2H, J=7 Hz), 2.95 (s, 3H),2.78 (m, 1H), 1.91 (m, 2H); MS (M+1) 296.1.

D. General Synthetic Procedure for Preparation of1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane hydrochlorides

Pursuant to steps e and f of Reaction Scheme 14, borane (1 M complex inTHF, 5 eq.) was cooled to <0° C. and a solution of3-methyl-1-(aryl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (1 eq.) in THF(10 vol.) added dropwise, maintaining the temperature <0° C. Thereactions were warmed to room temperature for 15 minutes then heated toreflux (67° C.) for 2 hours. The reactions were cooled to <0° C. andquenched with the dropwise addition of 6 M HCl (5 vol., temperaturemaintained <0° C.). Solvents were removed in vacuo and the resultingwhite residues made basic with the addition of 5 M NaOH (25 mL) andextracted with DCM (2×20 mL). The organics were washed with water (3×30mL) then concentrated in vacuo to −1 mL volume. The resulting oils werepurified by column chromatography (15 g silica, eluting with DCM then 5%MeOH in DCM) to give the crude free bases. Samples were dissolved indiethyl ether (1 mL) and 1 M HCl in ether (10 mL) was added. Theresulting white precipitates were stored at −20° C. for 16 hours thencentrifuged. Ether was decanted and the solids washed with a furtherthree portions of ether (material isolated by centrifugation and etherdecanted after each wash). Materials were dried in vacuo at 30° C. togive the required products as white solids. The compounds shown below(NMR data also listed below) were prepared using the general proceduresdescribed above:

Free base: ¹H NMR (300 MHz, CDCl₃) δ 7.07-6.95 (1H, m, ArH), 6.92-6.79(2H, m, ArH), 3.23-3.20 (1H, d, J=8.8 Hz, CH₂), 3.04-3.01 (1H, d, J=8.8Hz, CH₂), 2.48-2.42 (2H, m, CH₂), 2.32 (3H, s, NCH₃), 1.62-1.58 (1H, m,CH), 1.39-1.38 (1H, m, CH₂) 0.74-0.70 (1H, dd, J=8.1 Hz, 4.4 Hz, CH₂).

Hydrochloride salt: Yield=175 mg (28%); ¹H NMR (300 MHz, CDCl₃) δ 12.16(1H, br-s, N⁺H), 7.26-6.95 (3H, m, ArH), 3.95 (1H, br-s, CH₂), 3.80 (1H,br-s, CH₂), 3.53 (1H, br-s, CH₂), 3.42 (1H, br-s, CH₂), 2.92 (3H, s,NCH₃), 2.10 (1H, br-s, CH₂), 1.95 (1H, br-s, CH), 113 (1H, br-s, CH₂);¹³C NMR (75 MHz, CDCl₃) δ 151.67, 151.03, 148.51, 147.90, 134.70,123.77, 123.64, 117.64, 117.42, 116.88, 116.65, 60.10, 56.96, 41.12,30.63, 23.26, 15.29; MS (m/z) 210 [MH⁺]; LC purity 96.3%.

Free base: ¹H NMR (300 MHz, CDCl₃) δ 7.13-7.03 (2H, m, ArH), 6.80-6.75(1H, m, ArH), 3.28-3.25 (1H, d, J=8.9 Hz, CH₂), 3.08-3.05 (1H, d, J=8.8Hz, CH₂), 2.55-2.52 (1H, d, J=8.5 Hz, CH₂), 2.47-2.43 (1H, dd, J=8.8 Hz,3.3 Hz, CH₂) 2.36 (3H, s, NCH₃), 2.22 (3H, s, ArCH₃), 1.67-1.62 (1H, m,CH), 1.43-1.39 (1H, m, CH₂) 0.79-0.75 (1H, dd, J=8.1 Hz, 4.4 Hz, CH₂).

Hydrochloride salt: Yield=66 mg (30%); ¹H NMR (300 MHz, CDCl₃) δ 12.12(1H, br-s, N⁺H), 7.07-7.02 (1H, t, J=7.9 Hz, ArH), 6.87-6.80 (2H, m,ArH), 3.94-3.91 (1H, d, J=9.2 Hz, CH₂), 3.78-3.75 (1H, d, J=8.8 Hz,CH₂), 3.44-3.39 (1H, m, CH₂), 3.36-3.34 (1H, m, CH₂), 2.88 (3H, s,NCH₃), 2.14 (3H, s, ArCH₃), 2.07-2.04 (1H, m, CH₂), 1.91-1.88 (1H, m,CH), 1.10-1.05 (1H, obs t, J=7.6 Hz, CH₂); ¹³C NMR (75 MHz, CDCl₃) δ162.68, 159.43, 137.39, 137.29, 131.69, 131.61, 124.01, 123.79, 122.44,122.40, 113.92, 113.63, 59.88, 56.85, 40.75, 30.71, 23.17, 15.48, 13.91;MS (m/z) 206 [MH⁺]; LC purity 93.1%.

Free base: ¹H NMR (300 MHz, CDCl₃) δ 6.97-6.94 (1H, m, ArH), 6.93-6.88(2H, m, ArH), 3.28-3.25 (1H, d, J=8.4 Hz, CH₂), 3.08-3.05 (1H, d, J=8.5Hz, CH₂), 2.52-2.45 (2H, m, CH₂), 2.35 (3H, s, NCH₃), 2.24 (3H, s,ArCH₃), 1.64-1.59 (1H, m, CH), 1.38-1.35 (1H, obs t, J=4.3 Hz, CH₂)0.76-0.72 (1H, dd, J=8.1 Hz, 4.4 Hz, CH₂)—

Hydrochloride salt: Yield=134 mg (26%); ¹H NMR (300 MHz, CDCl₃) δ 12.21(1H, br-s, N⁺H), 6.99-6.93 (2H, m, ArH), 6.90-6.84 (1H, t, J=8.8 Hz,ArH), 3.98-3.93 (1H, dd, J=10.6 Hz, 5.1 Hz, CH₂), 3.83-3.78 (1H, dd,J=10.8 Hz, 4.9 Hz, CH₂), 3.41-3.34 (1H, m, CH₂), 3.27-3.21 (1H, obs t,J=9.4 Hz CH₂), 2.87-2.85 (3H, d, J=4.5 Hz, NCH₃), 2.18 (3H, s, ArCH₃)2.07-2.03 (1H, m, CH₂), 1.92-1.87 (1H, m, CH), 1.09-1.04 (1H, obs t,J=7.5 Hz, CH₂); ¹³C NMR (75 MHz, CDCl₃) δ 162.00, 158.75, 133.04,132.99, 130.45, 130.37, 126.18, 126.08, 125.33, 125.09, 115.32, 115.02,60.37, 56.99, 40.85, 30.71, 22.73, 15.25, 14.28; MS (m/z) 206 [MH⁺]; LCpurity 98.6%.

Free base: ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.13 (1H, m, ArH), 6.78-6.68(2H, m, ArH), 3.20-3.16 (1H, dd, J=8.5 Hz, 1.4 Hz, CH₂), 3.08-3.05 (1H,d, J=8.5 Hz, CH₂), 2.55-2.51 (1H, dd, J=8.8 Hz, 3.3 Hz, CH₂), 2.40-2.37(1H, d, J=8.4 Hz, CH₂), 2.32 (3H, s, NCH₃), 1.65-1.60 (1H, m, CH),1.35-1.32 (1H, obs t, J=4.3 Hz, CH₂) 0.72-0.68 (1H, dd, J=8.1 Hz, 4.4Hz, CH₂).

Hydrochloride salt: Yield=136 mg (19%); ¹H NMR (300 MHz, CDCl₃) δ 12.20(1H, br-s, N⁺H), 7.22-7.17 (1H, m, ArH), 6.89-6.75 (2H, m, ArH),3.94-3.85 (2H, m, CH₂), 3.37-3.35 (1H, d, J=8.1 Hz, CH₂), 3.17-3.14 (1H,d, J=10.6 Hz, CH₂), 2.85 (3H, s, NCH₃), 2.13 (1H, br-s, CH₂), 1.92-1.87(1H, m, CH), 1.18-1.13 (1H, obs t, J=7.9 Hz, CH₂); ¹³C NMR (75 MHz,CDCl₃) δ 164.29, 164.13, 163.75, 163.59, 160.97, 160.81, 160.45, 160.29,131.91, 131.85, 120.51, 120.27, 111.84, 111.50, 104.47, 104.13, 103.79,59.76, 56.90, 41.03, 26.69, 22.42, 13.37; MS (m/z) 210 [MH⁺]; LC purity95.1%.

Free base: ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.16 (3H, m, ArH), 3.16-3.13(1H, d, J=8.8 Hz, CH₂), 3.11-3.08 (1H, d, J=8.8 Hz, CH₂), 2.70-2.66 (1H,dd, J=8.8 Hz, 3.7 Hz, CH₂), 2.45-2.43 (1H, d, J=8.5 Hz, CH₂), 2.35 (3H,s, NCH₃), 1.66-1.61 (1H, m, CH), 1.41-1.38 (1H, obs t, J=4.4 Hz, CH₂)0.74-0.70 (1H, dd, J=8.1 Hz, 4.4 Hz, CH₂).

Free base: Yield=276 mg, (61%) as a white solid. MS(M+1) 254.2. ¹H NMR(CDCl₃) δ 7.62-7.68 (m, 2H), 7.54 (m, 1H), 7.22 (m, 1H), 7.08-7.14 (m,2H), 3.90 (s, 3H), 3.42 (m, 1H), 3.15 (m, 1H), 2.70 (m, 1H), 2.56 (m,1H), 2.42 (s, 3H), 1.77 (m, 1H), 1.48 (m, 1H), 0.91 (m, 1H).

Hydrochloride salt: Yield=155 mg, (77%) as a white solid. MS (M+1)254.2. ¹H NMR (CDCl₃) δ 12.56 (br s, 1H), 7.67 (m, 2H), 7.55 (m, 1H),7.21 (m, 1H), 7.14 (m, 1H), 7.08 (m, 1H), 4.14 (m, 1H), 3.93 (m, 1H),3.89 (s, 3H), 3.34 (m, 2H), 2.90 (d, 2H, J=5 Hz), 2.24 (m, 1H), 2.06 (m,1H), 1.26 (m, 1H). ¹³C NMR (CDCl₃) δ 158.18, 133.92, 132.89, 129.22,128.87, 127.83, 126.15, 125.43, 119.81, 105.85, 60.76, 57.52, 55.55,41.45, 31.77, 23.23, 16.11.

Free base: Yield=192 mg, (65%) as a white solid. ¹H NMR (CDCl₃) δ 7.64(m, 2H), 7.54 (m, 1H), 7.21 (m, 1H), 7.07-7.15 (m, 2H), 4.13 (q, 2H, J=7Hz), 3.41 (m, 1H), 3.15 (m, 1H), 2.69 (m, 1H), 2.56 (m, 1H), 2.42 (s,3H), 1.77 (m, 1H), 1.48 (m, 1H), 1.47 (t, 3H, J=7 Hz), 0.91 (m, 1H); MS(M+1) 268.2.

Hydrochloride salt: Yield=172 mg, (81%) as a white solid. ¹H NMR (CDCl₃)δ 12.50 (br s, 1H), 7.66 (m, 2H), 7.54 (m, 1H), 7.20 (m, 1H), 7.14 (m,1H), 7.07 (m, 1H), 4.14 (m, 1H), 4.10 (t, 2H, J=7 Hz), 3.93 (m, 1H),3.34 (m, 2H), 2.90 (d, 3H, J=5 Hz), 2.22 (m, 1H), 2.06 (m, 1H), 1.45 (t,3H, J=7 Hz), 1.26 (m, 1H). ¹³C NMR (CDCl₃) δ 157.50, 133.96, 132.76,129.17, 128.81, 127.79, 126.14, 125.37, 120.09, 106.61, 63.75, 60.77,57.54, 41.46, 31.77, 23.21, 16.09, 14.98; MS (M+1) 268.2.

EXAMPLE IX Preparation of 1-Aryl-3-ethyl-3-aza-bicyclo([3.1.0]hexaneHydrochlorides Using Reaction Scheme 15

A cooled (5° C.) solution of N-ethylmaleimide (20 g, 0.16 mole) incarbon tetrachloride (20 mL) under nitrogen was treated dropwise over 45min with bromine (23 g, 0.14 mole) at a rate to keep pot temp <10° C.The mixture was stirred at 5° C. for 2 hours. Dichloromethane (20 mL)was added to the reaction and N₂ was bubbled through the reaction for 15min to remove excess bromine. The reaction was blown dry with a steadystream of N₂ and then brought up in ethanol. Anhydrous sodium acetate(12.3 g, 0.15 mole) was added and the reaction was refluxed for 4 hours.The mixture was concentrated in vacuo and the residue taken up inmethylene chloride (300 mL), filtered and concentrated in vacuo to yieldan orange oil. Pure 3-bromo-1-ethylmaleimide was obtained fromrecrystallization in chloroform to yield a yellowish solid (26 g, 82%).NO MS (M+1) peak observed. ¹H NMR (CDCl₃) δ 1.20 (t, J=7.22 Hz, 3H),3.62 (q, J=7.22 Hz, 2H), 6.85 (s, 1H).

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (1.0 g, 5mmol) and 3,4-difluorophenylboronic acid (850 mg, 5.4 mmol) in dioxane(15 mL) under nitrogen was degassed with a stream of nitrogen for 10min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 45 min. The mixture was then cooled anddiluted with methylene chloride (50 mL). The mixture was filteredthrough Celite® (rinse filter cake with methylene chloride) and thebrown filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride and filtered through a column of silica gel (elutedwith methylene chloride) to afford a pale yellow solid, which wastriturated from cold petroleum ethers to afford arylmaleimideintermediate (973 mg, 84%) as a pale yellow solid.

A stirred suspension of sodium hydride oil dispersion (60%, 160 mg, 4.0mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.58 g, 4.5 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (937 mg, 4.0mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (429 mg, 42%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.09-1.16 (m, 3H) 1.21-1.31 (m, 1H) 1.73-1.87 (m, 2H) 2.72 (dd, J=8.00,3.90 Hz, 1H) 3.40-3.53 (m, 2H) 7.05-7.22 (m, 2H) 7.26-7.34 (m, 1H).

A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (429 mg, 1.7 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford 1-(3,4-difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (105 mg, 21%) as a white solid. MS (M+1) 224. ¹H NMR(CDCl₃) 1.08-1.19 (m, J=6.64, 6.64 Hz, 1H) 1.49 (t, 3H) 1.71-1.86 (m,1H) 1.90-2.03 (m, 1H) 2.30 (dd, 1H) 3.00-3.42 (m, 4H) 3.89 (dd, 1H) 4.06(dd, 1H) 6.69-7.20 (m, 3H). ¹³C NMR (CDCl₃) δ 10.99, 16.31, 22.96,30.42, 51.17, 55.07, 58.31, 116.85, 117.75, 123.82, 135.79, 148.65,149.29, 150.63, 151.28.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (1.09 g, 5mmol) and 3-chloro-4-fluorophenylboronic acid (945 mg, 5.4 mmol) indioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf). CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 45 min. The mixture was then cooled anddiluted with methylene chloride (50 mL). The mixture was filteredthrough Celite® (rinse filter cake with methylene chloride) and thebrown filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride and filtered through a column of silica gel (elutedwith methylene chloride) to afford a pale yellow solid, which wastriturated from cold petroleum ethers to afford arylmaleimideintermediate (1.0 g, 83%) as a pale yellow solid.

A stirred suspension of sodium hydride oil dispersion (60%, 160 mg, 3.95mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.56 g, 4.3 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (1.0 g, 3.95mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (567 mg, 54%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.09-1.16 (m, 3H) 1.21-1.31 (m, 1H) 1.73-1.87 (m, 2H) 2.72 (dd, J=8.00,3.90 Hz, 1H) 3.40-3.53 (m, 2H) 7.05-7.22(m, 2H) 7.26-7.34(m, 1H).

A stirred ice-cooled solution of 1.0N borane/THF (10.5 mL, 10.5 mmol)under nitrogen was treated dropwise with a solution of the abovebicyclic diimide intermediate (560 mg, 2.1 mmol) in anhydrous THF (10mL). The solution was stirred at room temperature for 15 min, refluxedfor 4 h, cooled on an ice bath, and carefully treated dropwise with 6NHCl (10 mL, vigorous evolution of gas). The solution was concentrated toa white solid, which was partitioned between 5N sodium hydroxide (25 mL)and ether (50 mL). The organic layer was separated and the aqueousextracted with ether (50 mL). The combined organic solution was washedwith water (25 mL), dried (Mg₂SO₄), and concentrated in vacuo. Theresidue was dissolved in methanol (23 mL), treated with 4N HCl/dioxane(7 mL), then stirred at room temperature for 16 h and at 55° C. for 4 h.The solution was concentrated in vacuo and the residue triturated fromether to afford1-(3-chloro-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (100 mg, 20%) as a white solid. MS (M+1) 240.1. ¹H NMR(CDCl₃) δ 1.13-1.20 (m, 1H) 1.51 (t, J=7.22 Hz, 3H) 1.93-2.02 (m, 1H)2.36 (dd, J=6.64, 4.69 Hz, 1H) 2.95-3.30 (m, 4H) 3.92 (dd, J=10.84, 5.17Hz, 1H) 4.10 (dd, J=10.93, 5.27 Hz, 1H) 7.01-7.15 (m, 2H) 7.23 (dd,J=6.74, 2.25 Hz, 1H). ¹³C NMR (CDCl₃) δ 11.22, 16.63, 22.99, 31.42,55.52, 58.68, 124.82, 126.25, 126.49, 126.96, 127.82, 129.06, 132.68,133.44, 135.59.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (1.0 g, 5mmol) and 3-fluoro-4-methylphenyl boronic acid (830 mg, 5.4 mmol) indioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 45 min. The mixture was then cooled anddiluted with methylene chloride (50 mL). The mixture was filteredthrough Celite® (rinse filter cake with methylene chloride) and thebrown filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride and filtered through a column of silica gel (elutedwith methylene chloride) to afford a pale yellow solid, which wastriturated from cold petroleum ethers to afford arylmaleimideintermediate (888 mg, 80%) as a pale yellow solid.

A stirred suspension of sodium hydride oil dispersion (60%, 152 mg, 3.8mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.59 g, 4.2 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (888 mg, 3.81mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (297 mg, 31%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.13 (t, J=7.13 Hz, 3H) 1.73-1.84 (m, 2H) 2.24-2.29 (m, J=1.95 Hz, 1H)2.68 (dd, J=8.00, 3.90 Hz, 1H) 3.42-3.53 (m, 2H) 7.01-7.12 (m, 2H) 7.18(t, J=7.91 Hz, 1H).

A stirred ice-cooled solution of 1.0N borane/THF (9.6 mL, 9.6 mmol)under nitrogen was treated dropwise with a solution of the abovebicyclic diimide intermediate (297 mg, 1.2 mmol) in anhydrous THF (10mL). The solution was stirred at room temperature for 15 min, refluxedfor 4 h, cooled on an ice bath, and carefully treated dropwise with 6NHCl (10 mL, vigorous evolution of gas). The solution was concentrated toa white solid, which was partitioned between 5N sodium hydroxide (25 mL)and ether (50 mL). The organic layer was separated and the aqueousextracted with ether (50 mL). The combined organic solution was washedwith water (25 mL), dried (Mg₂SO₄), and concentrated in vacuo. Theresidue was dissolved in methanol (23 mL), treated with 4N HCl/dioxane(7 mL), then stirred at room temperature for 16 h and at 55° C. for 4 h.The solution was concentrated in vacuo and the residue triturated fromether to afford1-(3-fluoro-4-methylphenyl)-3-ethyl-3-azabicyclo[3.1.0]hexanehydrochloride (165 mg, 63%) as a white solid. MS (M+1) 220. ¹H NMR(CDCl₃) □ 1.13 (t, J=7.61 Hz, 1H) 1.48 (t, J=7.22 Hz, 3H) 1.91-2.00 (m,1H) 2.20-2.23 (m, J=1.76 Hz, 3H) 2.25 (dd, J=6.64, 4.69 Hz, 1H)3.13-3.24 (m, 3H) 3.24-3.36 (m, 1H) 3.87 (dd, J=10.93, 5.27 Hz, 1H) 4.05(dd, J=10.84, 5.37 Hz, 1H) 6.76-6.88 (m, 2H) 7.03-7.16 (m, 1H). ¹³C NMR(CDCl₃) δ 11.13, 14.40, 16.54, 23.05, 30.69, 51.49, 55.26, 58.39,113.92, 122.62, 124.36, 132.11, 137.89, 160.27, 162.72.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (1.0 g, 5mmol) and 3-methyl-4-fluorophenyl boronic acid (830 mg, 5.4 mmol) indioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 45 min. The mixture was then cooled anddiluted with methylene chloride (50 mL). The mixture was filteredthrough Celite® (rinse filter cake with methylene chloride) and thebrown filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride and filtered through a column of silica gel (elutedwith methylene chloride) to afford a pale yellow solid, which wastriturated from cold petroleum ethers to afford arylmaleimideintermediate (982 mg, 88%) as a pale yellow solid.

A stirred suspension of sodium hydride oil dispersion (60%, 170 mg, 4.2mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.60 g, 4.6 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (982 mg, 4.2mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (460 mg, 50%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.13 (t, J=7.13 Hz, 3H) 1.73-1.84 (m, 2H) 2.24-2.29 (m, J=1.95 Hz, 1H)2.68 (dd, J=8.00, 3.90 Hz, 1H) 3.42-3.53 (m, 2H) 7.01-7.12 (m, 2H) 7.18(t, J=7.91 Hz, 1H).

A stirred ice-cooled solution of 1.0N borane/THF (15 mL, 15 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (470 mg, 1.9 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford 1-(3-methyl-4-fluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (400 mg, 89%) as a white solid. MS (M+1) 220. ¹H NMR(CDCl₃) δ 1.10 (t, J=7.61 Hz, 1H) 1.47 (t, J=7.22 Hz, 3H) 1.88-1.97 (m,1H) 2.18-2.21 (m, 1H) 2.21-2.23 (m, J=2.54, 2.54 Hz, 3H) 3.10-3.22 (m,3H) 3.23-3.33 (m, 1H) 3.86 (dd, J=11.03, 5.37 Hz, 1H) 4.03 (dd, J=10.93,5.47 Hz, 1H) 6.87-7.03 (m, 3H). ¹³C NMR (CDCl₃) δ 11.13, 14.76, 16.05,22.60, 30.71, 51.47, 55.39, 58.87, 115.61, 125.67, 126.44, 130.74,133.59, 159.54, 161.98.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (0.7 g, 3.43mmol) and 2,4-difluorophenyl boronic acid (0.85 g, 5.4 mmol) in dioxane(15 mL) under nitrogen was degassed with a stream of nitrogen for 10min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 0.5 h and at 45° C. for 30 min then at 65° C. for 45 min. Themixture was cooled and diluted with methylene chloride (50 mL). Themixture was filtered through Celite® (rinse filter cake with methylenechloride) and the brown filtrate concentrated in vacuo. The residue wasdissolved in methylene chloride and filtered through a column of silicagel (eluted with methylene chloride 60% and ethyl acetate 40%) to afforda yellowish solid, which was triturated from cold petroleum ethers toafford arylmaleimide intermediate (922 mg, 80%) as yellowish solid.

A stirred suspension of sodium hydride oil dispersion (60%, 155 mg, 3.89mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (922 mg, 3.89mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (460 mg, 59%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.14 (t, J=7.13 Hz, 3H) 1.76-1.83 (m, 1H) 1.83-1.93 (m, 1H) 2.61 (dd,J=8.40, 3.71 Hz, 1H) 3.41-3.55 (m, 2H) 6.77-6.95 (m, 2H) 7.27-7.37 (m,1H).

A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (460 mg, 2.2 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford 1-(2,4-difluorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (250 mg, 62%) as a white solid. MS (M+1) 224. ¹H NMR(CDCl₃) δ 1.15 (t, J=7.71 Hz, 1H) 1.46 (t, J=7.22 Hz, 3H) 1.84-1.93 (m,1H) 2.17-2.25 (m, 1H) 3.06-3.21 (m, 3H) 3.27-3.36(m, 1H) 3.84-3.99(m,2H) 6.68-6.88(m, 2H) 7.14-7.25(m, 1H). ¹³C NMR (CDCl₃) δ 11.04, 13.78,22.38, 26.60, 51.46, 55.16, 58.09, 104.50, 112.05, 132.29.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (0.7 g, 3.43mmol) and 2,4-diclorophenylboronic acid (1.03 g, 5.4 mmol) in dioxane(15 mL) under nitrogen was degassed with a stream of nitrogen for 10min, treated with cesium fluoride (1.6 g, 10.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 0.5 h and at 45° C. for 30 min then at 65° C. for 45 min. Themixture was cooled and diluted with methylene chloride (50 mL). Themixture was filtered through Celite® (rinse filter cake with methylenechloride) and the brown filtrate concentrated in vacuo. The residue wasdissolved in methylene chloride and filtered through a column of silicagel (eluted with methylene chloride 60% and ethyl acetate 40%) to afforda yellowish solid, which was triturated from cold petroleum ethers toafford arylmaleimide intermediate (1.32 g, 87%) as yellowish solid.

A stirred suspension of sodium hydride oil dispersion (60%, 165 mg, 4.1mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.58 g, 4.5 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (1.1 g, 4.1 mmol)was added in one portion and the mixture stirred at 50° C. for 3 h,cooled on an ice bath, and quenched with saturated ammonium chloride (10mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (603 mg, 52%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.15 (t, 3H) 1.86 (dd, J=4.88, 3.71 Hz, 1H) 1.93 (dd, J=8.20, 4.88 Hz,1H) 2.57 (dd, J=8.30, 3.81 Hz, 1H) 3.44-3.53 (m, 2H) 7.29 (d, J=1.17 Hz,2H) 7.45 (t, J=1.17 Hz, 1H).

A stirred ice-cooled solution of 1.0N borane/THF (5 mL, 5 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (200 mg, 0.7 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford 1-(2,4-dichlorophenyl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (115 mg, 47%) as a white solid. MS (M+1) 256.1. ¹H NMR(CDCl₃) δ 1.16-1.23 (m, 1H) 1.47 (t, J=6.44 Hz, 3H) 1.87-1.93 (m, 1H)2.23-2.31 (m, 1H) 3.10-3.28 (m, 3H) 3.36-3.48 (n, 1H) 3.81-3.98 (m, 2H)7.19-7.32 (m, 3H). ¹³C NMR (CDCl₃) δ 11.13, 14.34, 23.43, 30.37, 51.57,55.36, 57.48, 128.15, 129.96, 133.00, 133.69, 135.27, 136.11.

A stirred solution/suspension of 3-bromo-1-ethylmaleimide (1.0 g, 5mmol) and naphthalene-2-boronic acid (930 mg, 5.4 mmol) in dioxane (15mL) under nitrogen was degassed with a stream of nitrogen for 10 min,treated with cesium fluoride (1.6 g, 10.8 mmol) and Cl₂Pd(dppf).CH₂Cl₂(0.25 g, 0.3 mmol), then stirred at room temperature for 1 h and at 40°C. for 45 min. The mixture was then cooled and diluted with methylenechloride (50 mL). The mixture was filtered through Celite® (rinse filtercake with methylene chloride) and the brown filtrate concentrated invacuo. The residue was dissolved in methylene chloride and filteredthrough a column of silica gel (eluted with methylene chloride) toafford a pale yellow solid, which was triturated from cold petroleumethers to afford arylmaleimide intermediate (925 mg, 75%) as a paleyellow solid.

A stirred suspension of sodium hydride oil dispersion (60%, 145 mg, 3.68mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.52 g, 4.05 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (925 mg, 3.68mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (466 mg, 48%) as a very pale yellow oil. ¹H NMR (CDCl₃) δ1.16 (t, J=7.13 Hz, 3H) 1.82-1.90 (m, 1H) 1.95 (dd, J=8.20, 4.69 Hz, 1H)2.80 (dd, J=8.20, 3.71 Hz, 1H) 3.43-3.59 (m, 2H) 7.43-7.54 (m, 3H)7.73-7.92 (m, 4H).

A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (466 mg, 1.76 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford 1-(naphthalene-2-yl)-3-ethyl-3-azabicyclo[3.1.0]hexane,hydrochloride (110 mg, 20%) as a white solid. MS (M+1) 238. ¹H NMR(CDCl₃) δ 1.29 (t, J=7.42 Hz, 1H) 1.53 (t, J=6.44 Hz, 3H) 2.07-2.14 (m,1H) 2.33-2.41 (m, 1H) 3.16-3.26 (m, 2H) 3.26-3.38 (m, 2H) 3.95 (d, 1H)4.20 (d, J=7.22 Hz, 1H) 7.23 (s, 1H) 7.42-7.54 (m, 2H) 7.63 (s, 1H)7.73-7.86 (m, 3H). ¹³C NMR (CDCl₃) δ 158.83, 156.34, 135.62, 129.93,127.57, 121.54, 117.17, 59.78, 57.35, 53.99, 30.68, 23.06, 19.05, 16.29.

EXAMPLE X Preparation of 1-Aryl-3-isopropyl-3-aza-bicyclo[3.1.0]hexaneHydrochlorides Using Reaction Scheme 16

A cooled (5° C.) stirred solution of maleic anhydride (29.4 g, 0.30mole) in anhydrous ether (150 mL) under nitrogen was treated dropwiseover 45 min with a solution of isopropylamine (35.5 g, 0.60 mole) inanhydrous ether (100 mL) at a rate to keep the pot temp <20° C. Themixture was then stirred at 10° C. for 15 min, filtered, and the filtercake rinsed with anhydrous ether and dried in vacuo to afford a whitesolid. This was taken up in acetic anhydride (250 mL), treated withanhydrous sodium acetate (12.3 g, 0.15 mole), and heated to 75° C. withstirring for 4.5 h, then at 100° C. for 1.5 h. The mixture wasconcentrated in vacuo and the residue taken up in methylene chloride(300 mL), washed with saturated aqueous sodium bicarbonate (200 mL),water (200 mL), dried (MgSO₄), and concentrated in vacuo. The residuewas distilled (approx. 5 mm pressure) to afford two products; one anN-isopropylmaleimide that distilled at 82° C. (13.0 g), the other anacetate adduct of N-isopropylmaleimide that distilled at 154° C. (12.9g). The acetate adduct was dissolved in 4:1 acetonitrile/triethylamine(100 mL), heated to 65° C. for 4 h, then concentrated in vacuo. Theresidue was dissolved in methylene chloride and filtered through a padof silica gel (eluted with methylene chloride) to afford an additional3.5 g of N-isopropylmaleimide. Total yield was 16.5 g ofN-isopropylmaleimide (40%).

A stirred ice-cold solution of N-isopropylmaleimide (16.4 g, 0.118 mole)in carbon tetrachloride (12 mL) under nitrogen was treated dropwise withbromine (6.41 mL, 0.25 mole) at a rate to keep the pot temp <9° C., thenstirred at 3° C. for 2 h, during which time the mixture formed a solidcake. The cake was maintained under a stream of nitrogen to allow excessbromine and CCl₄ to evaporate. The reaction mixture was then placedunder vacuum to remove the remaining solvent. Ethanol (100 mL) was addedto the flask, followed by sodium acetate (11 g, 0.134 mole), and themixture was refluxed for 16 h with stirring. The cooled solution wasfiltered through Celite® (filter cake rinsed with methylene chloride),and the filtrate concentrated in vacuo, dissolved in methylene chloride,filtered through a pad of alumina (eluted with methylene chloride), andre-concentrated in vacuo. The residue was dissolved in 2:1 petroleumether/methylene chloride, loaded onto a column of silica gel, and elutedsuccessively with 2:1 petroleum ethers/CH₂Cl₂, 1:1 petroleumethers/CH₂Cl₂, and CH₂Cl₂ alone to afford the subject compound (16.45 g,64% yield) as a pale yellow, low melting solid. No MS (M+1) peakobserved. ¹H NMR (CDCl₃) δ 6.78 (s, 1H), 4.30-4.40 (m, 1H), 1.37 (d, 6H,J=8 Hz))

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 3,4-difluorophenylboronic acid (987 mg, 6.25 mmol)in dioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 3 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a pale yellow solid, which was trituratedfrom cold petroleum ethers to afford arylmaleimide intermediate (1.024g, 82%) as a very pale yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ7.83 (m, 1H), 7.67 (m, 1H), 7.24 (m, 1H), 6.64 (s, 1H), 4.39 (m, 1H),1.43 (d, 6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethylsulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (879 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (793 mg, 85%) as a white solid. No MS (M+1) peak. ¹H NMR(CDCl₃) δ 7.29 (m, 1H), 7.07-7.20 (m, 2H), 4.24 (m, 1H), 2.68 (m, 1H),1.71-1.76 (m, 2H), 1.34 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (21 mL, 21 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (780 mg, 2.94 mmol) in anhydrous THF (14 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (12mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (30 mL) andether (60 mL). The organic layer was separated and the aqueous extractedwith ether (60 mL). The combined organic solution was washed with water(2×35 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (30 mL), treated with 4N HCl/dioxane (10 mL),stirred at room temperature for 60 h (only 16 h needed), and at 55° C.for 4 h. The solution was concentrated in vacuo and the residue wastriturated from ether containing a little acetonitrile to afford1-(3,4-difluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (585 mg, 73%) as a white solid. MS (M+1) 238.2. ¹H NMR(CDCl₃) δ 7.08 (m, 2H), 6.92 (m, 1H), 4.02 (m, 1H), 3.84 (m, 1H), 3.35(m, 2H), 3.22 (m, 1H), 2.39 (m, 1H), 1.96 (m, 1H), 1.51 (d, 6H, J=6 Hz),1.10(m, 1H). ¹³C NMR(CDCl₃) δ 151.82, 149.34, 135.59, 123.85, 118.08,116.89, 59.75, 57.30, 53.97, 30.80, 23.19, 19.04, 16.34.

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 3-chloro-4-fluorophenylboronic acid (1.09 g, 6.25mmol) in dioxane (15 mL) under nitrogen was degassed with a stream ofnitrogen for 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 45 min The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a pale yellow solid, which was trituratedfrom cold petroleum ethers to afford arylmaleimide intermediate (1.10 g,82%) as a pale yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ 8.03 (m,1H), 7.80 (m, 1H), 7.20-7.30 (m, 1H), 6.65 (s, 1H), 4.40 (m, 1H), 1.43(d, 6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (937 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual solid was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,2:1, then 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (628 mg, 64%) as a very pale yellow oil. No MS (M+1) peak.¹H NMR (CDCl₃) δ 7.48 (m, 1H), 7.27 (m, 1H), 7.14 (m, 1H), 4.23 (m, 1H),2.69 (m, 1H), 1.74 (m, 2H), 1.34 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (620 mg, 2.2 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 16 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford1-(3-chloro-4-fluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexanehydrochloride (520 mg, 81%) as a white solid. MS (M+1) 254.1. ¹H NMR(CDCl₃) δ 7.25 (m, 1H), 7.08 (m, 2H), 4.04 (m, 1H), 3.85 (m, 1H), 3.35(m, 2H), 3.21 (m, 1H), 2.39 (m, 1H), 1.97 (m, 1H), 1.50 (d, 6H, J=7 Hz),1.10 (m, 1H). ¹³C NMR (CDCl₃) δ 158.83, 156.34, 135.62, 129.93, 127.57,121.54, 117.17, 59.78, 57.35, 53.99, 30.68, 23.06, 19.05, 16.29.

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 3-fluoro-4-methylphenylboronic acid (962 mg, 6.25mmol) in dioxane (15 mL) under nitrogen was degassed with a stream ofnitrogen for 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 1 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a yellow solid, which was triturated frompetroleum ethers to afford arylmaleimide intermediate (1.11 g, 90%) as apale yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ 7.60 (m, 2H), 7.24(m, 1H), 6.62 (s, 1H), 4.39 (m, 1H), 2.32 (br s, 3H), 1.43 (d, 6H, J=7Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (866 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual oil was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 2:1, and 3:1 methylene chloride/heptane to afford bicyclic diimideintermediate (633 mg, 69%) as a white solid. MS (M+1) 262.1. ¹H NMR(CDCl₃) δ 7.17 (m, 1H), 7.09 (m, 1H), 7.04 (m, 1H), 4.24 (m, 1H), 2.64(m, 1H), 2.26 (br s, 3H), 1.70-1.80 (m, 2H), 1.34 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (17 mL, 17 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (619 mg, 2.37 mmol) in anhydrous THF (11 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (10mL, vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (50 mL). The combined organic solution was washed with water(2×30 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (23 mL), treated with 4N HCl/dioxane (7 mL), thenstirred at room temperature for 60 h (only requires 14 h) and at 55° C.for 4 h. The solution was concentrated in vacuo and the residuetriturated from ether to afford1-(3-fluoro-4-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (538 mg, 84%) as a white solid. MS (M+1) 234.2. ¹H NMR(CDCl₃) δ 7.11 (m, 1H), 6.82 (m, 2H), 4.02 (m, 1H), 3.83 (m, 1H),3.32(m, 2H), 3.23 (m, 1H), 2.35 (m, 1H), 2.21 (s, 3H), 1.94 (s, 1H),1.51 (d, 6H, J=7 Hz), 1.10(m, 1H). ¹³C NMR(CDCl₃) δ 132.13, 124.39,124.22, 122.68, 114.06, 113.84, 59.68, 57.22, 53.98, 30.88, 23.16,19.02, 16.58, 14.41.

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 4-fluoro-3-methylphenylboronic acid (962 mg, 6.25mmol) in dioxane (15 mL) under nitrogen was degassed with a stream ofnitrogen for 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 1 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a yellow solid, which was triturated fromcold petroleum ethers to afford arylmaleimide intermediate (1.14 g, 92%)as a very pale yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ 7.77 (m,1H), 7.72 (m, 1H), 7.06 (m, 1H), 6.58 (s, 1H), 4.38 (m, 1H), 2.32 (br s,3H), 1.43 (d, 6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (866 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual oil was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, then 2:1 methylene chloride/heptane to afford bicyclic diimideintermediate (510 mg, 56%) as a colorless oil. No MS (M+1) peak. ¹H NMR(CDCl₃) δ 7.23 (m, 1H), 7.16 (m, 1H), 6.99 (m, 1H), 4.23 (m, 1H), 2.63(m, 1H), 2.27 (br s, 3H), 1.72 (m, 2H), 1.34 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (7.5 mL, 7.5 mmol)under N₂ was treated dropwise with a solution of the above bicyclicdiimide intermediate (268 mg, 1.026 mmol) in anhydrous THF (5 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (5 mL,vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (15 mL) andether (30 mL). The organic layer was separated and the aqueous extractedwith ether (30 mL). The combined organic solution was washed with water(2×15 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (12 mL), treated with 4N HCl/dioxane (4 mL), andstirred at room temperature for 14 h and at 55° C. for 4 h. The solutionwas concentrated in vacuo and the residue triturated from ether toafford1-(4-fluoro-3-methylphenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (230 mg, 83%) as a white solid. MS (M+1) 234.2. ¹H NMR(CDCl₃) δ 6.96 (m, 3H), 4.03 (m, 1H), 3.86 (m, 1H), 3.29 (m, 2H),3.17(m, 1H), 2.34 (m, 1H), 2.24 (s, 3H), 1.93 (m, 1H), 1.52 (d, 6H, J=7Hz), 1.09 (m, 1H). ¹³C NMR (CDCl₃) δ 161.52, 159.56, 133.69, 130.66,126.39, 125.50, 115.48, 59.48, 57.57, 53.98, 30.70, 22.57, 18.87, 15.83,14.58.

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 2,4-difluorophenylboronic acid (987 mg, 6.25 mmol)in dioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 60° C. for 1 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a pale yellow solid, which was trituratedfrom cold petroleum ethers to afford arylmaleimide intermediate (941,75%) as a very pale yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ8.33 (m, 1H), 6.88-7.02 (m, 2H), 6.85 (m, 1H), 4.40 (m, 1H), 1.43 (d,6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (879 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residue was dissolved in 1:1 methylenechloride/heptane and loaded onto a silica gel column and eluted with1:1, 3:2, and 2:1 methylene chloride/heptane to afford bicyclic diimideintermediate (292 mg, 32%) as a pale yellow solid. MS (M+1) 266.1. ¹HNMR (CDCl₃) δ 7.31 (m, 1H), 6.82-6.92 (m, 2H), 4.24 (m, 1H), 2.57 (m,1H), 1.84 (m, 1H), 1.74 (m, 1H), 1.35 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (8 mL, 8 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (290 mg, 1.093 mmol) in anhydrous THF (5 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (5 mL,vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (15 mL) andether (30 mL). The organic layer was separated and the aqueous extractedwith ether (30 mL). The combined organic solution was washed with water(20 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (15 mL), treated with 4N HCl/dioxane (5 mL), andstirred at room temperature for 60 h (needed only 14 h) and at 55° C.for 4 h. The solution was concentrated in vacuo and the residuetriturated from ether to afford1-(2,4-difluorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (280 mg, 94%) as a white solid. MS (M+1) 238.2. ¹H NMR(CDCl₃) δ 7.21 (m, 1H), 6.82 (m, 2H), 3.88 (m, 2H), 3.39 (m, 1H), 3.31(m, 1H), 3.18 (m, 1H), 2.32 (m, 1H), 1.86 (m, 1H), 1.49 (m, 6H), 1.14(m, 1H). ¹³C NMR (CDCl₃) δ 164.19, 161.70, 132.36, 121.03, 112.13,104.48, 59.33, 56.11, 53.61, 26.77, 22.61, 18.82, 13.69

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and 2,4-dichlorophenylboronic acid (1.19 g, 6.25 mmol)in dioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 60° C. for 1 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a pale yellow oil, which was trituratedfrom cold petroleum ethers to afford arylmaleimide intermediate (1.038g, 73%) as a white solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ 7.68 (m,1H), 7.52 (m, 1H), 7.34 (m, 1H), 6.94 (s, 1H), 4.40 (m, 1H), 1.44 (d,6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 140 mg, 3.5mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.55 g, 4.25 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (995 mg, 3.5mmol) was added in one portion and the mixture stirred at 50° C. for 3h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×50 mL), and thecombined extracts washed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residual oil was dissolved in 1:1 methylenechloride/heptane, loaded onto a silica gel column and eluted with 1:1,then 2:1 methylene chloride/heptane to afford bicyclic diimideintermediate (523 mg, 50%) as a pale yellow solid. No MS (M+1) peak. ¹HNMR (CDCl₃) δ 7.44 (m, 1H), 7.28 (m, 2H), 4.25 (m, 1H), 2.51 (m, 1H),1.90 (m, 1H), 1.81 (m, 1H), 1.35 (d, 6H, J=7 Hz).

A stirred ice-cooled solution of 1.0N borane/THF (12 mL, 12 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (498 mg, 1.67 mmol) in anhydrous THF (8 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 4 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (7 mL,vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (20 mL) andether (40 mL). The organic layer was separated and the aqueous extractedwith ether (40 mL). The combined organic solution was washed with water(2×25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residue wasdissolved in methanol (15 mL), treated with 4N HCl/dioxane (5 mL), andstirred at room temperature for 60 h (needed only 14 h) and at 55° C.for 4 h. The solution was concentrated in vacuo and the residuetriturated from ether to afford1-(2,4-dichlorophenyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (347 mg, 68%) as a white solid. MS (M+1) 270.1. ¹H NMR(CDCl₃) δ 7.39 (d, 1H, J=2 Hz), 7.29 (d, 1H, J=8 Hz), 7.23 (dd, 1H, J=8Hz, 2 Hz), 3.83 (m, 2H), 3.48 (m, 1H), 3.30 (m, 2H), 2.39 (m, 1H), 1.88(m, 1H), 1.50 (m, 6H), 1.16 (m, 1H). ¹³C NMR (CDCl₃) δ 136.06, 135.20,133.78, 133.76, 129.92, 128.12, 59.36, 56.03, 53.73, 30.46, 23.51,18.94, 14.25.

A stirred solution/suspension of 3-bromo-1-(1-methylethyl)maleimide(1.09 g, 5 mmol) and naphthalene-2-boronic acid (1.08 g, 6.25 mmol) indioxane (15 mL) under nitrogen was degassed with a stream of nitrogenfor 10 min, treated with cesium fluoride (1.8 g, 11.8 mmol) andCl₂Pd(dppf).CH₂Cl₂ (0.25 g, 0.3 mmol), then stirred at room temperaturefor 1 h and at 40° C. for 2 h. The mixture was then cooled and dilutedwith methylene chloride (50 mL). The mixture was filtered throughCelite® (rinse filter cake with methylene chloride) and the brownfiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and filtered through a column of silica gel (eluted withmethylene chloride) to afford a solid, which was triturated frompetroleum ethers to afford the arylmaleimide intermediate (1.045 g, 79%)as a bright yellow solid. No MS (M+1) peak. ¹H NMR (CDCl₃) δ 8.67 (br s,1H), 7.75-7.95 (m, 4H), 7.54 (m, 2H), 6.76 (s, 1H), 4.44 (m, 1H), 1.47(d, 6H, J=7 Hz).

A stirred suspension of sodium hydride oil dispersion (60%, 120 mg, 3.0mmol) in anhydrous tetrahydrofuran (25 mL) under nitrogen was treatedwith trimethyl-sulfoxonium chloride (0.52 g, 4.0 mmol), then refluxedfor 2.5 h and cooled (50° C.). The above arylmaleimide (796 mg, 3.0mmol) was added in one portion and the mixture stirred at 50° C. for 2h, cooled on an ice bath, and quenched with saturated ammonium chloride(10 mL). The product mixture was extracted with ether (2×40 mL) and thecombined extracts were rinsed with water (30 mL), dried (MgSO₄), andconcentrated in vacuo. The residue was dissolved in petroleum etherscontaining a little methylene chloride, loaded onto a silica gel column,and eluted with 15% ethyl acetate/petroleum ethers to afford bicyclicdiimide intermediate (577 mg, 69%) as an orange solid. MS (M+1) 280.2.¹H NMR (CDCl₃) δ 7.80-7.90 (m, 4H), 7.50 (m, 3H), 4.28 (m, 1H), 2.77 (m,1H), 1.90 (m, 1H), 1.81 (m, 1H), 1.38 (m, 6H).

A stirred ice-cooled solution of 1.0N borane/THF (16 mL, 16 mmol) undernitrogen was treated dropwise with a solution of the above bicyclicdiimide intermediate (560 mg, 2.0 mmol) in anhydrous THF (10 mL). Thesolution was stirred at room temperature for 15 min, refluxed for 8 h,cooled on an ice bath, and carefully treated dropwise with 6N HCl (7 mL,vigorous evolution of gas). The solution was concentrated to a whitesolid, which was partitioned between 5N sodium hydroxide (25 mL) andether (50 mL). The organic layer was separated and the aqueous extractedwith ether (2×25 mL). The combined organic solution was washed withwater (25 mL), dried (Mg₂SO₄), and concentrated in vacuo. The residuewas dissolved in methanol (20 mL), treated with 4N HCl/dioxane (7 mL),and stirred at room temperature for 14 h and at 55° C. for 4 h. Thesolution was concentrated in vacuo and the residue triturated from etherto afford 1-(2-naphthyl)-3-(2-propyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (337 mg, 67%) as a white solid. MS (M+1) 252.2. ¹H NMR(CDCl₃) δ 7.81 (m, 3H), 7.63 (br s, 1H), 7.50 (m, 2H), 7.24 (m, 1H),4.18 (m, 1H), 3.94 (m, 1H), 3.35 (m, 3H), 2.49 (m, 1H), 2.11 (m, 1H),1.57 (d, 6H, J=6 Hz), 1.27 (m, 1H). ¹³C NMR (CDCl₃) δ 135.66, 133.21,132.41, 128.77, 127.65, 127.54, 126.67, 126.20, 126.07, 124.75, 59.49,57.23, 54.01, 31.29, 22.93, 18.90, 16.31.

A solution of bromomaleic anhydride (Aldrich, 20.0 g, 0.113 mole) inanhydrous tetrahydrofuran (100 mL) under nitrogen was treated dropwisewith a solution of 3,4-dimethoxybenzylamine (20.0 g, 0.1196 mole) inanhydrous THF (40 mL) over 30 min, and the stirred mixture was thenrefluxed for 3 h and maintained at room temperature for 20 h. Themixture was concentrated in vacuo, suspended in acetic anhydride (135mL), treated with anhydrous sodium acetate (6.15 g, 75 mmol), and heatedto 50° C. with stirring under nitrogen for 4 h (solids dissolved after afew minutes). The mixture was concentrated in vacuo and dissolved inmethylene chloride (300 mL). The solution was washed with saturatedaqueous sodium bicarbonate (150 mL), then with water (150 mL), dried(Na₂SO₄), and concentrated in vacuo to a brown residue. This wasdissolved in methylene chloride and passed through a column of silicagel (˜400 mL volume) and eluted with methylene chloride to afford a tansolid, which was recrystallized from ethyl acetate/heptane (2 crops) toafford 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (24.75 g, 67%) as a paletan solid. NO MS (M+1) peak. ¹H NMR (CDCl₃) δ 6.89-6.94 (m, 2H), 6.84(s, 1H), 6.78 (d, 1H, J=8 Hz), 4.63 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.14 g,3.5 mmol) and 3,4-difluorophenylboronic acid (0.71 g, 4.5 mmol) inanhydrous dioxane (10 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (1.3 g, 8.5 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.17 g, 0.21 mmol), stirred 1 h at roomtemperature, then 2 h at 40° C. The mixture was cooled, diluted withmethylene chloride (50 mL), stirred a few minutes, filtered throughCelite ® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 3% ethylacetate/methylene chloride to afford a yellow solid, which wastriturated from petroleum ethers to afford the intermediatearylmaleimide (954 mg, 76%) as a very pale yellow solid. NO MS (M+1)peak. ¹H NMR (CDCl₃) δ 7.84 (m, 1H), 7.68 (m, 1H), 7.24 (m, 1H),6.93-6.99 (m, 2H), 6.80 (m, 1H), 6.70 (s, 1H), 4.66 (s, 2H), 3.87 (s,3H), 3.84 (s, 3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(431 mg, 3.35 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.4N, 1.2 mL, 2.85mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (900 mg, 2.5 mmol) inanhydrous THF (10 mL) was heated to 50° C., then added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h, and cooled on an ice bath. Saturated aqueous ammoniumchloride (2 mL) was added to quench, and the mixture was diluted withmethylene chloride (75 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 1%, 2%, then 3% ethyl acetate/methylenechloride to afford the intermediate bicyclic diimide (602 mg, 65%) as apale yellow gum. MS (M+1) 374.2. ¹H NMR (CDCl₃) δ 7.28 (m, 1H), 7.15 (m,1H), 7.08 (m, 1H), 6.87-6.92 (m, 2H), 6.78 (m, 1H), 4.50 (m, 2H), 3.85(s, 2H), 3.84 (s, 2H), 2.72 (m, 1H), 1.72 (m, 2H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF(10.6 mL, 10.6 mmol) under nitrogen was treated slowly with a solutionof the above intermediate bicyclic diimide (597 mg, 1.6 mmol) inanhydrous THF (7 mL), stirred 1 h at room temperature, refluxed for 6 h,and cooled (5° C.). Water (0.4 mL), 15% sodium hydroxide (0.4 mL), andwater (1.2 mL) were carefully added dropwise, followed by additional THFto facilitate stirring. The suspension was stirred 15 min, filteredthrough Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in methylene chloride,loaded onto a silica gel column, and eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediate dimethoxybenzylbicyclic amine (345 mg, 63%) as a colorless viscous oil. MS (M+1) 346.2.¹H NMR (CDCl₃) δ 7.03 (m, 1H), 6.86-6.95 (m, 2H), 6.78-6.85 (m, 3H),3.88 (s, 3H), 3.86 (s, 3H), 3.60 (m, 2H), 3.22 (m, 1H), 3.05 (m, 1H),2.53 (m, 2H), 1.64 (m, 1H), 1.52 (m, 1H), 0.75 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (345 mg,1.00 mmol) and anhydrous potassium carbonate (311 mg, 2.25 mmol) inanhydrous methylene chloride (8 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (322 mg, 2.25mmol), closed, and stirred at 45° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (10 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (3.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether, filtered through Celite®, and the filtrate treated with 2NHCl/ether (0.75 mL, 1.5 mmol). The suspension was stirred, the solidsalt collected by filtration, rinsed with ether, and dried in vacuo toafford 1-(3,4-difluorophenyl)-3-azabicyclo[3.1.0]hexane, hydrochloride(118 mg, 51%) as a white solid. MS (M+1) 196.0. ¹H NMR (CDCl₃) δ 10.31(br s, 1H), 9.83 (br s, 1H), 7.11 (m, 1H), 7.00 (m, 1H), 6.93 (m, 1H),3.75 (m, 1H), 3.50-3.70 (m, 3H), 1.94 (m, 1H), 1.60 (m, 1H), 1.20 (m,1H). ¹³C NMR(CDCl₃)δ 151.83, 149.30, 135.20, 123.66, 118.07, 116.84,50.91, 47.73, 31.02, 23.61, 15.74.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.63 g,5.0 mmol) and 4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.35 g,6.5 mmol) in anhydrous dioxane (15 mL) under nitrogen was degassed over10 min with a stream of nitrogen, then treated with cesium fluoride (2.0g, 13.2 mmol) and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.25 g, 0.30 mmol),stirred 1 h at room temperature, then 2 h at 40° C. The mixture wascooled, diluted with methylene chloride (70 mL), stirred a few minutes,filtered through Celite® (rinse with methylene chloride), and thefiltrate concentrated in vacuo. The residue was dissolved in methylenechloride and loaded onto a silica gel column and the product eluted withmethylene chloride to afford product, which was triturated frompetroleum ethers to afford the intermediate arylmaleimide (1.05 g, 51%)as a yellow solid. NO MS (M+1) peak. ¹H NMR (CDCl₃) δ 7.69 (m, 1H), 7.36(m, 1H), 7.04 (m, 1H), 6.92-6.99 (m, 3H), 6.79 (m, 1H), 4.68 (s, 2H),3.87 (s, 3H), 3.85 (s, 3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(434 mg, 3.375 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.4N, 1.17 mL, 2.80mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (1.023 g, 2.5 mmol) inanhydrous THF (10 mL) was heated to 50° C. and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h, and cooled on an ice bath. Saturated aqueous ammoniumchloride (3 mL) was added to quench, and the mixture was diluted withmethylene chloride (75 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 2% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (602 mg, 65%) as a pale yellowfoam. MS (M+1) 423.9. ¹H NMR (CDCl₃) δ 7.64 (m, 1H), 7.56 (m, 1H), 7.28(m, 1H), 6.88 (m, 2H), 6.79 (m, 1H), 4.53 (m, 2H), 3.85 (br s, 6H), 2.71(m, 1H), 1.91 (m, 1H), 1.76 (m, 1H).

An ice-cooled, stirred solution of 1N borane/THF (7.5 mL, 7.5 mmol)under nitrogen was treated dropwise with a solution of the aboveintermediate bicyclic diimide (390 mg, 0.92 mmol) in anhydroustetrahydrofuran (4 mL), then stirred for 45 min at room temperature andfor 4 h at reflux and cooled on an ice bath. 6N HCl (5 mL) was carefullyadded dropwise, and the mixture was concentrated in vacuo and the whitesolid residue partitioned between 5N NaOH (15 mL) and ether (50 mL). Theorganic layer was separated and the aqueous was extracted with ether(2×30 mL). The combined organic solution was dried (MgSO₄), concentratedin vacuo, dissolved in methanol (15 mL), treated with 4N HCl/dioxane (5mL), then stirred at room temperature for 18 h and at 60° C. for 4 h.The solution was concentrated in vacuo and the residue dissolved inmethanol (25 mL), treated with DOWEX® 550A-OH resin (3 g), stirred for15 min, filtered, and the filtrate concentrated in vacuo to afford theintermediate dimethoxybenzyl bicyclic amine (272 mg, 75%) as a colorlessglass. MS (M+1) 396.2. ¹H NMR (CDCl₃) δ 7.43 (m, 2H), 7.12 (m, 1H), 6.86(m, 1H), 6.78-6.82 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.59 (m, 2H),3.19 (m, 1H), 3.08 (m, 1H), 2.62 (m, 1H), 2.43 (m, 1H), 1.74 (m, 1H),1.50 (m, 1H), 0.77 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (276 mg,0.698 mmol) and anhydrous potassium carbonate (207 mg, 1.5 mmol) inanhydrous methylene chloride (5.5 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.21 mL, 1.93mmol), closed, and stirred at 40° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (10 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (1.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride, loaded onto a silica gel column, and eluted with 5%ethanol/methylene chloride, then with 10% (9:1ethanol/ammonia)/methylene chloride to afford an oil, which wasdissolved in ether (3 mL), treated with 2N HCl/ether (0.5 mL, 1.0 mmol),stirred a few minutes, filtered, rinsed with ether, collected, and driedin vacuo to afford1-(4-fluoro-3-trifluoromethylphenyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (91 mg, 46%) as a white solid. MS (M+1) 246.0. ¹H NMR(CDCl₃) δ 10.35 (br s, 1H), 9.87 (br s, 1H), 7.55 (m, 1H), 7.46 (m, 1H),7.21 (m, 1H), 3.60-3.80 (m, 3H), 3.51 (m, 1H), 2.03 (m, 1H), 1.68 (m,1H), 1.22 (m, 1H). ¹³C NMR (CDCl₃) δ 134.80, 126.95, 126.56, 124.44,123.64, 120.93, 50.19, 47.27, 26.85, 22.28, 13.56.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.14 g,3.5 mmol) and 3-fluoro-4-methoxyphenylboronic acid (765 mg, 4.5 mmol) inanhydrous dioxane (10 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (1.3 g, 8.5 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.17 g, 0.21 mmol), stirred 1 h at roomtemperature, then 2 h at 40° C. The mixture was cooled, diluted withmethylene chloride (50 mL), stirred a few minutes, filtered throughCelite® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 3% ethylacetate/methylene chloride to afford product, which was triturated frompetroleum ethers to afford the intermediate arylmaleimide (1.123 g, 86%)as a yellow solid. MS (M+1) 372.1. ¹H NMR (CDCl₃) δ 7.76 (m, 1H), 7.71(m, 1H), 7.01 (m, 1H), 6.93-6.99 (m, 2H), 6.80 (m, 1H), 6.60 (s, 1H),4.65 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(515 mg, 4.00 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.4N, 1.42 mL, 3.4mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (1.114 g, 3.0 mmol) inanhydrous THF (13 mL) was heated to 50° C., and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 1.5 h, and cooled on an ice bath. Saturated aqueous ammoniumchloride (2 mL) was added to quench, and the mixture was diluted withmethylene chloride (75 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 2%, then 3% ethyl acetate/methylene chlorideto afford the intermediate bicyclic diimide (622 mg, 54%) as a palebeige solid. MS (M+1) 386.2. ¹H NMR (CDCl₃) δ 7.14 (m, 1H), 7.07 (m,1H), 6.94 (m, 1H), 6.87-6.92 (m, 2H), 6.78 (m, 1H), 4.50 (m, 2H), 3.87(s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 2.67 (m, 1H), 1.74 (m, 1H), 1.67(m, 1H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF(10.6 mL, 10.6 mmol) under nitrogen was treated slowly with a solutionof the above intermediate bicyclic diimide (617 mg, 1.6 mmol) inanhydrous THF (7 mL), stirred 1 h at room temperature, refluxed for 6 h,and cooled (5° C.). Water (0.4 mL), 15% sodium hydroxide (0.4 mL), andwater (1.2 mL) were carefully added dropwise, followed by additional THFto facilitate stirring. The suspension was stirred 20 min, filteredthrough Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in methylene chloride,loaded onto a silica gel column, and eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediate dimethoxybenzylbicyclic amine (362 mg, 63%) as a colorless viscous oil. MS (M+1) 358.3.¹H NMR (CDCl₃) δ 6.78-6.88 (m, 6H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84 (s,3H), 3.59 (m, 2H), 3.20 (m, 1H), 3.04 (m, 1H), 2.53 (m, 2H), 1.61 (m,1H), 1.46 (m, 1H), 0.73 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (358 mg,1.00 mmol) and anhydrous potassium carbonate (311 mg, 2.25 mmol) inanhydrous methylene chloride (8 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (322 mg, 2.25mmol), closed, and stirred at 45° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (10 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (3.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether, filtered through Celite®, and the filtrate treated with 2NHCl/ether (0.75 mL, 1.5 mmol). The suspension was stirred for awhile,the solid salt collected by filtration, rinsed with ether, and dried invacuo to afford 1-(3-fluoro-4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (125 mg, 51%) as a white solid. MS (M+1) 208.0. ¹H NMR(CDCl₃) δ 10.27 (br s, 1H), 9.76 (br s, 1H), 6.88-6.95 (m, 3H), 3.86 (s,3H), 3.72 (m, 1H), 3.40-3.65 (m, 3H), 1.89 (m, 1H), 1.54 (m, 1H), 1.18(m, 1H). ¹³C NMR(CDCl₃) δ 153.72, 147.27, 131.04, 123.51, 115.58,113.92, 56.56, 51.08, 47.80, 30.95, 23.32, 15.39.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g,4.0 mmol) and 3-fluoro-4-methylphenylboronic acid (770 mg, 5.0 mmol) inanhydrous dioxane (12 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.20 g, 0.245 mmol), stirred 1 h atroom temperature, then 2 h at 40° C. The mixture was cooled, dilutedwith methylene chloride (60 mL), stirred a few minutes, filtered throughCelite®0 (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 2% ethylacetate/methylene chloride to afford the intermediate arylmaleimide(1.12 g, 79%) as a yellow solid. MS (M+1) 356.1. ¹H NMR (CDCl₃) δ 7.63(m, 1H), 7.59 (m, 1H), 7.24 (m, 1H), 6.94-6.99 (m, 2H), 6.80 (m, 1H),6.68 (s, 1H), 4.65 (s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 2.31 (s, 3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(534 mg, 4.15 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.5N, 1.4 mL, 3.45mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (1.10 g, 3.1 mmol) inanhydrous THF (10 mL) was heated to 50° C., and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h, and cooled on an ice bath. Saturated aqueous ammoniumchloride (2 mL) was added to quench, and the mixture was diluted withmethylene chloride (60 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 2% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (615 mg, 54%) as a viscous paleyellow oil. MS (M+1) 370.2. ¹H NMR (CDCl₃) δ 7.16 (m, 1H), 7.08 (m, 1H),7.02 (m, 1H), 6.87-6.93 (m, 2H), 6.78 (m, 1H), 4.50 (m, 2H), 3.85 (s,3H), 3.84 (s, 3H), 2.69 (m, 1H), 2.25 (br s, 3H), 1.76 (m, 1H), 1.68 (m,1H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF(11.5 mL, 11.5 mmol) under nitrogen was treated slowly with a solutionof the above intermediate bicyclic diimide (650 mg, 1.76 mmol) inanhydrous THF (10 mL), stirred 1 h at room temperature, refluxed for 6h, and cooled (5° C.). Water (0.45 mL), 15% sodium hydroxide (0.45 mL),and water (1.35 mL) were carefully added dropwise, followed byadditional THF to facilitate stirring. The suspension was stirred 15min, filtered through Celite® (filter cake rinsed with THF), and thefiltrate concentrated in vacuo. The residue was dissolved in methylenechloride, loaded onto a silica gel column, and eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediate dimethoxybenzylbicyclic amine (347 mg, 58%) as a colorless viscous oil. MS (M+1) 342.2.¹H NMR (CDCl₃) δ 7.05 (m, 1H), 6.88 (m, 1H), 6.73-6.83 (m, 4H), 3.88 (s,3H), 3.87 (s, 3H), 3.59 (m, 2H), 3.23 (m, 1H), 3.04 (m, 3H), 2.54 (m,2H), 2.21 (br s, 3H), 1.65 (m, 1H), 1.50 (m, 1H), 0.76 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (336 mg,0.984 mmol) and anhydrous potassium carbonate (286 mg, 2.07 mmol) inanhydrous methylene chloride (8 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.29 mL, 2.71mmol), closed, and stirred at 40° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (12 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (2.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether, filtered through Celite®, and the filtrate treated with 2NHCl/ether (0.50 mL, 1.0 mmol). The suspension was stirred, the solidsalt collected by filtration, rinsed with ether, and dried in vacuo toafford 1-(3-fluoro-4-methylphenyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (127 mg, 57%) as a white solid. MS (M+1) 192.1. ¹H NMR(CDCl₃) δ 10.29 (br s, 1H), 9.80 (br s, 1H), 7.11 (m, 1H), 6.78-6.88 (m,2H), 3.75 (m, 1H), 3.50-3.65 (m, 3H), 2.22 (s, 3H), 1.92 (m, 1H), 1.57(m, 1H), 1.19 (m, 1H). ¹³C NMR (CDCl₃) δ 162.72, 137.90, 132.05, 124.30,122.66, 114.08, 50.75, 47.72, 31.06, 23.57, 15.85, 14.38.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.0 g,3.06 mmol) and 4-(4-fluoro-3-methyl)phenyl boronic acid (0.52 g, 3.4mmol) in anhydrous dioxane (10 mL) under nitrogen was degassed over 10min with a stream of nitrogen, then treated with cesium fluoride (1.3 g,8.5 mmol) and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.17 g, 0.21 mmol), stirred 1h at room temperature, then 2 h at 40° C. The mixture was cooled,diluted with methylene chloride (50 mL), stirred a few minutes, filteredthrough Celite 4 (rinse with methylene chloride), and the filtrateconcentrated in vacuo. The residue was dissolved in methylene chlorideand loaded onto a silica gel column and the product eluted with 3% ethylacetate/methylene chloride to afford a yellow solid, which wastriturated from petroleum ethers to afford the intermediatearylmaleimide (940 g, 79%) as a pale yellow solid.

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(370 mg, 2.86 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.4N, 1.1 mL, 2.03mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (0.94 g, 2.6 mmol) inanhydrous THF (10 mL) was heated to 50° C., and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h and cooled on an ice bath. Saturated aqueous ammoniumchloride (1 mL) was added to quench, and the mixture was diluted withmethylene chloride (75 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 3% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (400 mg, 50%) as a very paleyellow viscous oil. ¹H NMR (CDCl₃) δ 1.63-1.70 (m, 1H) 1.74 (dd, J=8.16,4.63 Hz, 1H) 2.21-2.31 (m, J=1.87 Hz, 3H) 2.67 (dd, J=8.22, 3.58 Hz, 1H)3.85 (d, J=2.76 Hz, 6H) 4.50 (dd, 2H) 6.82-7.03 (m, 2H) 7.08-7.24 (m,1H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF(3.6 mL, 10 mmol) under nitrogen was treated slowly with a solution ofthe above intermediate bicyclic diimide (400 mg, 1.2 mmol) in anhydrousTHF (7 mL), stirred 1 h at room temperature, refluxed for 6 h, andcooled (5° C.). Water (0.4 mL), 15% sodium hydroxide (0.4 mL), and water(1.2 mL) were carefully added dropwise, followed by additional THF tofacilitate stirring. The suspension was stirred 15 min, filtered throughCelite® (filter cake rinsed with THF), and the filtrate concentrated invacuo. The residue was dissolved in methylene chloride, loaded onto asilica gel column, and eluted with 3:1 methylene chloride/ethyl acetateto afford the intermediate dimethoxybenzyl bicyclic amine (280 mg, 58%)as a colorless viscous oil.

A mixture of the intermediate dimethoxybenzyl bicyclic amine (280 mg,0.76 mmol) and anhydrous potassium carbonate (215 mg, 1.55 mmol) inanhydrous methylene chloride (5 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.221 mL, 1.55mmol), closed, and stirred at 45° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (7 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (2.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether, filtered through Celite®, and the filtrate treated with 2NHCl/ether (0.6 mL, 1.2 mmol). The suspension was stirred a few minutes,the solid salt collected by filtration, rinsed with ether, and dried invacuo to afford 1-(4-fluoro-3-methylphenyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (100 mg, 47%) as a light beige solid. MS (M+1) 192.1. ¹HNMR (CDCl₃) δ 1.10 (t, J=7.61 Hz, 1H) 1.88-1.97 (m, 1H) 2.18-2.21 (m,1H) 2.21-2.23 (m, J=2.54, 2.54 Hz, 3H) 3.10-3.22 (m, 3H) 3.23-3.33 (m,1H) 3.86 (dd, J=1.03, 5.37 Hz, 1H) 4.03 (dd, J=10.93, 5.47 Hz, 1H)6.87-7.03 (m, 3H). ¹³C NMR (CDCl₃) δ 16.05, 22.60, 30.71, 51.47, 55.39,58.87, 115.61, 125.67, 126.44, 130.74, 133.59, 159.54, 161.98.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.0 g,3.06 mmol) and 2-naphthaleneboronic acid (0.59 g, 3.4 mmol) in anhydrousdioxane (10 mL) under nitrogen was degassed over 10 min with a stream ofnitrogen, then treated with cesium fluoride (1.3 g, 8.5 mmol) andCl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.17 g, 0.21 mmol), stirred 1 h at roomtemperature, then 2 h at 40° C. The mixture was cooled, diluted withmethylene chloride (50 mL), stirred a few minutes, filtered throughCelite® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 3% ethylacetate/methylene chloride to afford a yellow solid, which wastriturated from petroleum ethers to afford the intermediatearylmaleimide (690 g, 83%) as a pale yellow solid.

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(261 mg, 2.03 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.4N, 1.1 mL, 2.03mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (0.690 g, 2.6 mmol) inanhydrous THF (10 mL) was heated to 50° C. and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h and cooled on an ice bath. Saturated aqueous ammoniumchloride (1 mL) was added to quench, and the mixture was diluted withmethylene chloride (75 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 3% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (400 mg, 50%) as a very paleyellow viscous oil. ¹H NMR (CDCl₃) δ 1.78 (dd, J=4.59, 3.61 Hz, 1H) 1.91(dd, J=8.20, 4.69 Hz, 1H) 2.81 (dd, J=8.20, 3.71 Hz, 1H) 3.86 (d, J=4.30Hz, 6H) 4.54 (dd, 2H) 7.38-7.55 (m, 3H) 7.74-7.90 (m, 4H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF(3.6 mL, 10 mmol) under nitrogen was treated slowly with a solution ofthe above intermediate bicyclic diimide (360 mg, 1.0 mmol) in anhydrousTHF (7 mL), stirred 1 h at room temperature, refluxed for 6 h, andcooled (5° C.). Water (0.4 mL), 15% sodium hydroxide (0.4 mL), and water(1.2 mL) were carefully added dropwise, followed by additional THF tofacilitate stirring. The suspension was stirred 15 min, filtered throughCelite® (filter cake rinsed with THF), and the filtrate concentrated invacuo. The residue was dissolved in methylene chloride, loaded onto asilica gel column, and eluted with 3:1 methylene chloride/ethyl acetateto afford the intermediate dimethoxybenzyl bicyclic amine (350 mg, 55%)as a colorless viscous oil.

A mixture of the intermediate dimethoxybenzyl bicyclic amine (340 mg,0.95 mmol) and anhydrous potassium carbonate (290 mg, 2.1 mmol) inanhydrous methylene chloride (5 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.301 mL, 2.2mmol), closed, and stirred at 45° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (7 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (2.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether, filtered through Celite®, and the filtrate treated with 2NHCl/ether (0.6 mL, 1.2 mmol). The suspension was stirred a few minutes,the solid salt collected by filtration, rinsed with ether, and dried invacuo to afford 1-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane,hydrochloride (95 mg, 53%) as a light beige solid. MS (M+1) 210.1. ¹HNMR (DMSO-d₆) δ 1.14-1.23 (m, 1H) 1.49 (t, J=5.27 Hz, 1H) 2.13-2.27 (m,1H) 3.30-3.43 (m, 1H) 3.57 (d, J=7.81 Hz, 2H) 3.62-3.81 (m, 1H) 7.35(dd, J=8.59, 1.76 Hz, 1H) 7.39-7.53 (m, 2H) 7.71-7.91 (m, 4H). ¹³C NMR(DMSO-d₆) δ 16.44, 24.13, 31.37, 47.45, 49.92, 125.43, 125.74, 126.40,127.03, 128.10, 128.74, 132.38, 133.55, 137.64,

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g,4.0 mmol) and 6-methoxynaphthalene-2-boronic acid (1.01 g, 5.0 mmol) inanhydrous dioxane (12 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.20 g, 0.245 mmol), stirred 1 h atroom temperature, then 2 h at 40° C. The mixture was cooled, dilutedwith methylene chloride (60 mL), stirred a few minutes, filtered throughCelite® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 2% ethylacetate/methylene chloride to afford the intermediate arylmaleimide(1.10 g, 68%) as a yellow solid. MS (M+1) 404.2. ¹H NMR (CDCl₃) δ 8.62(m, 1H), 7.82 (m, 1H), 7.75 (m, 2H), 7.18 (m, 1H), 7.12 (m, 1H),6.97-7.02 (m, 2H), 6.81 (m, 1H), 6.76 (s, 1H), 4.69 (s, 2H), 3.94 (s,3H), 3.88 (s, 3H), 3.85 (s, 3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(482 mg, 3.75 mmol) in anhydrous tetrahydrofuran (12 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.5N, 1.2 mL, 3.00mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (1.09 g, 2.7 mmol) inanhydrous THF (12 mL) was heated to 50° C. and added quickly in oneportion to the above heated suspension. The mixture was then stirred at50° C. for 2 h and cooled on an ice bath. Saturated aqueous ammoniumchloride (2 mL) was added to quench, and the mixture was diluted withmethylene chloride (60 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 2% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (543 mg, 48%) as a pale orangesolid. MS (M+1) 418.2. ¹H NMR (CDCl₃) δ 7.78 (m, 1H), 7.67-7.75 (m, 2H),7.42 (m, 1H), 7.15 (m, 1H), 7.11 (m, 1H), 6.90-6.95 (m, 2H), 6.79 (m,1H), 4.54 (m, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 2.77 (m,1H), 1.88 (m, 1H), 1.75 (m, 1H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF (8mL, 8 mmol) under nitrogen was treated slowly with a solution of theabove intermediate bicyclic diimide (534 mg, 1.28 mmol) in anhydrous THF(6 mL), stirred 1 h at room temperature, refluxed for 6 h, and cooled(5° C.). Water (0.3 mL), 15% sodium hydroxide (0.3 mL), and water (0.9mL) were carefully added dropwise, followed by additional THF tofacilitate stirring. The suspension was stirred 15 min, filtered throughCelite® (filter cake rinsed with THF), and the filtrate concentrated invacuo. The residue was dissolved in methylene chloride, loaded onto asilica gel column, and eluted with 3:1 methylene chloride/ethyl acetateto afford the intermediate dimethoxybenzyl bicyclic amine (345 mg, 69%)as a white solid. MS (M+1) 390.2. ¹H NMR (CDCl₃) δ 7.64 (m, 2H), 7.52(m, 1H), 7.20 (m, 1H), 7.07-7.13 (m, 2H), 6.92 (m, 1H), 6.79-6.87 (m,2H), 3.90 (brs, 6H), 3.87 (s, 3H), 3.64 (m, 2H), 3.35 (m, 1H), 3.11 (m,1H), 2.70 (m, 1H), 2.58 (m, 1H), 1.78 (m, 1H), 1.56 (m, 1H), 0.87 (m,1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (325 mg,0.8344 mmol) and anhydrous potassium carbonate (243 mg, 1.76 mmol) inanhydrous methylene chloride (6.5 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.25 mL, 2.3mmol), closed, and stirred at 40° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (10 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (1.0 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was taken up inether containing a little methylene chloride, filtered through Celite®,and the filtrate treated with 2N HCl/ether (0.60 mL, 1.2 mmol). Thesuspension was stirred and the solid salt collected by filtration,rinsed with ether, suspended in acetonitrile, filtered, collected anddried in vacuo to afford1-(6-methoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride(151 mg, 66%) as a white solid. MS (M+1) 240.1. ¹H NMR (DMSO-d₆) δ δ9.90 (br s, 1H), 9.57 (br s, 1H), 7.73 (m, 3H), 7.31 (m, 1H), 7.26 (m,1H), 7.13 (m, 1H), 3.83 (s, 3H), 3.71 (m, 1H), 3.45-3.55 (m, 2H), 3.39(m, 1H), 2.14 (m, 1H), 1.43 (m, 1H), 1.14 (m, 1H). ¹³C NMR (DMSO-d₆) δ157.78, 134.96, 133.67, 129.58, 128.96, 127.66, 125.96, 125.74, 119.53,106.41, 55.82, 50.17, 47.55, 31.24, 23.87, 16.09.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (1.31 g,4.0 mmol) and 6-ethoxynaphthalene-2-boronic acid (1.08 g, 5.0 mmol) inanhydrous dioxane (12 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (1.5 g, 9.9 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.20 g, 0.245 mmol), stirred 1 h atroom temperature, then 2 h at 40° C. The mixture was cooled, dilutedwith methylene chloride (60 mL), stirred a few minutes, filtered throughCelite® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 2% ethylacetate/methylene chloride to afford the intermediate arylmaleimide(1.36 g, 81%) as a yellow solid. No MS (M+1) peak observed. ¹H NMR(CDCl₃) δ 8.62 (m, 1H), 7.81 (m, 1H), 7.74 (m, 2H), 7.17 (m, 1H), 7.10(m, 1H), 6.96-7.02 (m, 2H), 6.81 (m, 1H), 6.75 (s, 1H), 4.69 (s, 2H),4.16 (q, 2H, J=7 Hz), 3.88 (s, 3H), 3.84 (s, 3H), 1.48 (t, 3H, J=7 Hz).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(515 mg, 4.00 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.5N, 1.32 mL, 3.30mmol) and gradually warmed to 50° C. over 30 minutes. Meanwhile, asolution of the intermediate arylmaleimide (1.23 g, 2.95 mmol) inanhydrous THF (10 mL) was heated to 50° C., then added quickly in oneportion to the above heated suspension, and the mixture was stirred at50° C. for 2 h, then cooled on an ice bath. Saturated aqueous ammoniumchloride (3 mL) was added to quench, and the mixture was diluted withmethylene chloride (70 mL), dried (MgSO₄), filtered through Celite®(rinse with methylene chloride), and concentrated in vacuo. The residuewas dissolved in methylene chloride, loaded onto a silica gel column,and the product eluted with 2% ethyl acetate/methylene chloride toafford the intermediate bicyclic diimide (700 mg, 55%) as a pale orangeviscous oil. MS (M+1) 432.2. ¹H NMR (CDCl₃) δ 7.77 (m, 1H), 7.70 (m,2H), 7.41 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.90-6.95 (m, 2H), 6.79(m, 1H), 4.54 (m, 2H), 4.14 (q, 2H, J=7 Hz), 3.86 (s, 3H), 3.85 (s, 3H),2.77 (m, 1H), 1.88 (m, 1H), 1.75 (m, 1H), 1.47 (t, 3H, J=7 Hz).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF (11mL, 11 mmol) under nitrogen was treated slowly with a solution of theabove intermediate bicyclic diimide (690 mg, 1.60 mmol) in anhydrous THF(10 mL), stirred 1 h at room temperature, refluxed for 6 h, and cooled(5° C.). Water (0.45 mL), 15% sodium hydroxide (0.45 mL), and water(1.35 mL) were carefully added dropwise, followed by additional THF tofacilitate stirring. The suspension was stirred 15 min, filtered throughCelite® (filter cake rinsed with THF), and the filtrate concentrated invacuo. The residue was dissolved in methylene chloride, loaded onto asilica gel column, and eluted with 4:1 methylene chloride/ethyl acetateto afford the intermediate dimethoxybenzyl bicyclic amine (415 mg, 64%)as a white solid. MS (M+1) 404.8. ¹H NMR (CDCl₃) δ 7.63 (m, 2H), 7.51(m, 1H), 7.19 (m, 1H), 7.06-7.13 (m, 2H), 6.91 (m, 1H), 6.85 (m, 1H),6.81 (m, 1H), 4.13 (q, 2H, J=7 Hz), 3.89 (s, 3H), 3.87 (s, 3H), 3.63 (m,2H), 3.35 (m, 1H), 3.10 (m, 1H), 2.70 (m, 1H), 2.58 (m, 1H), 1.77 (m,1H), 1.56 (m, 1H), 1.46 (t, 3H, J=7 Hz), 0.87 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (403 mg,1.00 mmol) and anhydrous potassium carbonate (290 mg, 2.1 mmol) inanhydrous methylene chloride (8 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.30 mL, 2.75mmol), closed, and stirred at 40° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (12 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (1.5 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was dissolved inmethylene chloride, loaded onto a silica gel column, and eluted with 10%(9:1 ethanol/ammonia)/methylene chloride to afford a white solid. Thiswas taken up in anhydrous ether containing a little methylene chloride,treated with 2N HCl/ether (0.6 mL, 1.2 mmol), stirred, filtered,collected, and dried in vacuo to afford1-(6-ethoxynaphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride(148 mg, 51%) as a white solid. MS (M+1) 254.1. ¹H NMR (DMSO-d6) δ 9.93(br s, 1H), 9.62 (br s, 1H), 7.73 (m, 3H), 7.31 (m, 1H), 7.25 (m, 1H),7.12 (m, 1H), 4.10 (q, 2H, J=7 Hz), 3.71 (m, 1H), 3.51 (m, 2H), 3.38 (m,1H), 2.15 (m, 1H), 1.44 (m, 1H), 1.36 (t, 3H, J=7 Hz), 1.14 (m, 1H). ¹³CNMR(DMSO-d6) δ 156.11, 133.98, 132.81, 128.71, 128.27, 127.98, 126.73,125.04, 118.89, 106.21, 62.84, 49.27, 46.64, 30.36, 22.96, 15.38, 14.54.

A stirred solution of 3-bromo-1-(3,4-dimethoxybenzyl)maleimide (3.26 g,10.0 mmol) and 4-methylnaphthalene-1-boronic acid (2.33 g, 12.5 mmol) inanhydrous dioxane (30 mL) under nitrogen was degassed over 10 min with astream of nitrogen, then treated with cesium fluoride (4.0 g, 26 mmol)and Cl₂Pd(dppf).CH₂Cl₂ (Aldrich, 0.50 g, 0.61 mmol), stirred 1 h at roomtemperature, then 2 h at 40° C. The mixture was cooled, diluted withmethylene chloride (125 mL), stirred a few minutes, filtered throughCelite® (rinse with methylene chloride), and the filtrate concentratedin vacuo. The residue was dissolved in methylene chloride and loadedonto a silica gel column and the product eluted with 3% ethylacetate/methylene chloride to afford a solid, which was triturated frompetroleum ethers to afford the intermediate arylmaleimide (3.555 g, 92%)as a yellow solid. MS (M+1) 388.2. ¹H NMR (CDCl₃) δ 8.07 (m, 1H), 8.00(m, 1H), 7.50-7.62 (m, 2H), 7.39 (m, 1H), 7.00-7.05 (m, 2H), 6.82 (m,1H), 6.78 (s, 1H), 4.74 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.73 (s,3H).

A cooled (−20° C.) stirred solution of trimethylsulfoxonium chloride(1.48 g, 11.5 mmol) in anhydrous tetrahydrofuran (35 mL) under nitrogenwas treated dropwise with n-butyllithium/hexane (2.5N, 4.0 mL, 10 mmol)and gradually warmed to 50° C. over 30 minutes. Meanwhile, a solution ofthe intermediate arylmaleimide (3.50 g, 9.0 mmol) in anhydrous THF (35mL) was heated to 50° C. and added quickly in one portion to the aboveheated suspension. The mixture was then stirred at 50° C. for 2 h andcooled on an ice bath. Saturated aqueous ammonium chloride (5 mL) wasadded to quench, and the mixture was diluted with methylene chloride(200 mL), dried (MgSO₄), filtered through Celite® (rinse with methylenechloride), and concentrated in vacuo. The residue was dissolved inmethylene chloride, loaded onto a silica gel column, and the producteluted with 2% ethyl acetate/methylene chloride to afford firstrecovered starting material (680 mg), then the intermediate bicyclicdiimide (411 mg, 14% based on recovered starting material) as a pale tansolid. MS (M+1) 402.2. ¹H NMR (CDCl₃) δ 8.04 (m, 1H), 7.78 (m, 1H), 7.55(m, 1H), 7.45 (m, 1H), 7.36 (m, 1H), 7.28 (m, 1H), 6.92-6.98 (m, 2H),6.80 (m, 1H), 4.58 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.71 (m, 1H),2.69 (s, 3H), 1.95 (m, 1H), 1.90 (m, 1H).

A cooled (5° C.) stirred solution of 1N lithium aluminum hydride/THF (6mL, 6 mmol) under nitrogen was treated slowly with a solution of theabove intermediate bicyclic diimide (370 mg, 0.922 mmol) in anhydrousTHF (5 mL), stirred 1 h at room temperature, refluxed for 6 h, andcooled (5° C.). Water (0.23 mL), 15% sodium hydroxide (0.23 mL), andwater (0.70 mL) were carefully added dropwise, followed by additionalTHF to facilitate stirring. The suspension was stirred 15 min, filteredthrough Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in methylene chloride,loaded onto a silica gel column, and eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediate dimethoxybenzylbicyclic amine (252 mg, 73%) as a viscous colorless oil. MS (M+1) 374.3.¹H NMR (CDCl₃) δ 8.35 (m, 1H), 8.00 (m, 1H), 7.51 (m, 2H), 7.37 (m, 1H),7.24 (m, 1H), 6.90 (m, 1H), 6.76-6.84 (m, 2H), 3.88 (s, 3H), 3.86 (s,3H), 3.62 (m, 2H), 3.32 (m, 1H), 3.20 (m, 1H), 2.82 (m, 1H), 2.67 (s,3H), 2.55 (m, 1H), 1.76 (m, 1H), 1.62 (m, 1H), 0.80 (m, 1H).

A mixture of the intermediate dimethoxybenzyl bicyclic amine (240 mg,0.643 mmol) and anhydrous potassium carbonate (187 mg, 1.35 mmol) inanhydrous methylene chloride (5 mL) in a pressure tube equipped with astirbar was treated with 1-chloroethyl chloroformate (0.19 mL, 1.77mmol), closed, and stirred at 40° C. for 4 h. The tube was cooled,opened, and the contents filtered (rinse with methylene chloride), andthe filtrate concentrated in vacuo. The residue was dissolved inmethanol (8 mL), refluxed for 1 h, cooled, treated with DOWEX® 550A-OHresin (1 g, prerinsed with methanol), stirred a few minutes, filtered,and the filtrate concentrated in vacuo. The residue was dissolved inether, treated with 2.0N HCl/ether (0.4 mL, 0.8 mmol), the suspensionstirred a few minutes, filtered, rinsed with ether, collected, and driedin vacuo to afford1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride(149 mg, 89%) as a white solid. MS (M+1) 224.1. ¹H NMR (CDCl₃) δ 10.35(br s, 1H), 9.93 (br s, 1H), 8.12 (m, 1H), 8.03 (m, 1H), 7.56 (m, 2H),7.37 (m, 1H), 7.25 (m, 1H), 3.86 (m, 2H), 3.74 (m, 1H), 3.50 (m, 1H),2.67 (s, 3H), 2.06 (m, 1H), 1.78 (m, 1H), 1.24 (m, 1H). ¹³C NMR (CDCl₃)δ 135.42, 133.17, 131.95, 126.68, 126.40, 126.15, 125.33, 124.70, 51.94,48.04, 30.87, 22.44, 19.74, 14.76.

An ice-cooled (3° C.) stirred suspension of sodium amide (460 mg, 11.5mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was treatedwith a solution of 3-fluoro-4-(trifluoromethoxy)phenylacetonitrile (1.10g, 5.0 mmol) in anhydrous THF (5 mL) and stirred at room temperature for2 h, then recooled on an ice bath. Epichlorohydrin (0.52 mL, 6.0 mmol)was added via syringe in one portion, and the mixture was stirred atroom temperature for 1 h, cooled on an ice bath, and quenched withsaturated aqueous ammonium chloride (5 mL). The product mixture wastaken up in ethyl acetate (70 mL) and the organic layer was separated.The aqueous was extracted with ethyl acetate (15 mL), and the combinedorganic solution was dried (MgSO₄), concentrated in vacuo, dissolved inmethylene chloride, and loaded onto a silica gel column. The product waseluted with 3:1 methylene chloride/ethyl acetate to afford theintermediate hydroxymethylcyclopropylnitrile (887 mg, 65%) as a paleyellow viscous oil (3:1 syn/anti isomers by NMR). The compound wassomewhat impure, but used as is.

An ice-cooled (3° C.) stirred solution of 1N LAH/THF (4.5 mL, 4.5 mmol)under nitrogen was treated dropwise with a solution of the intermediatehydroxymethylcyclopropylnitrile (826 mg, 3.00 mmol) and the mixture wasstirred on an ice bath for 2 h, then carefully quenched with water (0.17mL), 15% sodium hydroxide (0.17 mL), and water (0.50 mL). The suspensionwas diluted with THF to facilitate stirring, then stirred 15 min,filtered through Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in anhydrous1,2-dichloroethane (14 mL) under nitrogen, cooled (3° C.), and treateddropwise with thionyl chloride (0.235 mL, 3.2 mmol). After stirring atroom temperature for 3 h, the solution was concentrated in vacuo and theresidue taken up in water (10 mL) and made basic with 5N sodiumhydroxide (3 mL). The aqueous solution was extracted with methylenechloride (4×20 mL) and the combined organic solution washed with water(30 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue wasdissolved in methylene chloride and loaded onto a silica gel column andeluted with 10% (9:1 ethanol/ammonia)/methylene chloride to afford thebicyclic amine free base (149 mg, 19%) as a pale yellow oil. MS (M+1)262.1. Compound carried through below was somewhat impure, but was usedas is.

A stirred solution of the bicyclic amine (144 mg, 0.55 mmol) inanhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL, 11.0mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford1-(3-fluoro-4-trifluoromethoxyphenyl)-3-azabicyclo[3.1.0]hexane,hydrochloride (107 mg, 65%) as a white solid. MS (M+1) 262.1. ¹H NMR(CDCl₃) δ 10.35 (br s, 1H), 9.89 (br s, 1H), 7.26 (m, 1H), 6.97-7.07 (m,2H), 3.78 (m, 1H), 3.55-3.70 (m, 3H), 1.99 (m, 1H), 1.65 (m, 1H),1.24(m, 1H). ¹³C NMR(CDCl₃) δ 155.76, 153.23, 139.09, 124.15, 123.28,116.30, 50.35, 47.44, 30.80, 23.74, 15.92.

An ice-cooled (3° C.) stirred suspension of sodium amide (2.3 g, 60mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was treatedwith a solution of 1-naphthaleneacetonitrile (5 g, 30 mmol) in anhydrousTHF (5 mL) and stirred at room temperature for 2 h, then recooled on anice bath. Epichlorohydrin (2.3 mL, 30 mmol) was added via syringe in oneportion, and the mixture was stirred at room temperature for 1 h, cooledon an ice bath, and quenched with saturated aqueous ammonium chloride (5mL). The product mixture was taken up in ethyl acetate (70 mL) and theorganic layer was separated. The aqueous was extracted with ethylacetate (15 mL), and the combined organic solution was dried (MgSO₄),concentrated in vacuo, dissolved in methylene chloride, and loaded ontoa silica gel column. The product was eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediatehydroxymethylcyclopropyl-nitrile (2 g, 30%) as a pale yellow viscous oil(3:1 syn/anti isomers by NMR).

An ice-cooled (3° C.) stirred solution of 1N LAH/THF (5.6 mL, 11.2 mmol)under nitrogen was treated dropwise with a solution of the intermediatehydroxymethylcyclopropylnitrile (2.0 g, 8.97 mmol) and the mixture wasstirred on an ice bath for 2 h, then carefully quenched with water (0.17mL), 15% sodium hydroxide (0.17 mL), and water (0.50 mL). The suspensionwas diluted with THF to facilitate stirring, then stirred 15 min,filtered through Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in anhydrous1,2-dichloroethane (14 mL) under nitrogen, cooled (3° C.), and treateddropwise with thionyl chloride (0.235 mL, 3.2 mmol). After stirring atroom temperature for 3 h, the solution was concentrated in vacuo and theresidue taken up in water (10 mL) and made basic with 5N sodiumhydroxide (3 mL). The aqueous solution was extracted with methylenechloride (4×20 mL) and the combined organic solution washed with water(30 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue wasdissolved in methylene chloride and loaded onto a silica gel column andeluted with 10% (9:1 ethanol/ammonia)/methylene chloride to afford thebicyclic amine free base (600 mg, 73%) as a pale yellow oil.

A stirred solution of the bicyclic amine (100 mg, 3.96 mmol) inanhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL, 1.0mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride (100 mg,85%) as a white solid. MS (M+1) 211.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.02-1.10 (m, 1H) 1.58 (t, J=5.08 Hz, 1H) 2.05-2.16 (m, 1H) 3.24 (d,J=10.93 Hz, 1H) 3.48 (dd, J=11.42, 5.95 Hz, 1H) 3.69 (dd, J=11.23, 5.95Hz, 1H) 3.71-3.82 (m, 1H) 7.46 (dd, J=8.20, 7.03 Hz, 1H) 7.50-7.58 (m,1H) 7.56-7.65 (m, 2H) 7.82-7.89 (m, 1H) 7.95 (d, J=7.42 Hz, 1H) 8.10 (d,J=8.40 Hz, 1H). ¹³C NMR (DMSO-d₆) δ 14.28, 22.74, 30.75, 47.76, 51.73,124.72, 126.29, 126.62, 127.23, 128.89, 129.47, 132.81, 134.08, 135.16.

An ice-cooled (3° C.) stirred suspension of 1M sodiumhexamethyldisilazane (17.2 mL, 17.2 mmol) in anhydrous tetrahydrofuran(15 mL) under nitrogen was treated with a solution of4-fluoronaphthalen-1-acetonitrile (1.6 g, 8.6 mmol) in anhydrous THF (5mL) and stirred at room temperature for 2 h, then recooled on an icebath. Epichlorohydrin (0.75 mL, 9.5 mmol) was added via syringe in oneportion, and the mixture was stirred at room temperature for 1 h, cooledon an ice bath, and quenched with saturated aqueous ammonium chloride (5mL). The product mixture was taken up in ethyl acetate (70 mL) and theorganic layer was separated. The aqueous was extracted with ethylacetate (15 mL), and the combined organic solution was dried (MgSO₄),concentrated in vacuo, dissolved in methylene chloride, and loaded ontoa silica gel column. The product was eluted with 3:1 methylenechloride/ethyl acetate to afford the intermediatehydroxymethylcyclopropylnitrile (1 g, 50%) as a pale yellow viscous oil(3:1 syn/anti isomers by NMR).

An ice-cooled (3° C.) stirred solution of 1N LAH/THF (2.6 mL, 5.2 mmol)under nitrogen was treated dropwise with a solution of the intermediatehydroxymethylcyclopropylnitrile (10 g, 4.2 mmol) and the mixture wasstirred on an ice bath for 2 h, then carefully quenched with water (0.17mL), 15% sodium hydroxide (0.17 mL), and water (0.50 mL). The suspensionwas diluted with THF to facilitate stirring, then stirred 15 min,filtered through Celite® (filter cake rinsed with THF), and the filtrateconcentrated in vacuo. The residue was dissolved in anhydrous1,2-dichloroethane (14 mL) under nitrogen, cooled (3° C.), and treateddropwise with thionyl chloride (0.235 mL, 3.2 mmol). After stirring atroom temperature for 3 h, the solution was concentrated in vacuo and theresidue taken up in water (10 mL) and basified with 5N sodium hydroxide(3 mL). The aqueous solution was extracted with methylene chloride (4×20mL) and the combined organic solution washed with water (30 mL), dried(Na₂SO₄), and concentrated in vacuo. The residue was dissolved inmethylene chloride and loaded onto a silica gel column and eluted with10% (9:1 ethanol/ammonia)/methylene chloride to afford the bicyclicamine free base (400 mg, 40%) as a pale yellow oil.

A stirred solution of the bicyclic amine (100 mg, 0.44 mmol) inanhydrous ether (5 mL) was treated with 2.0N HCl/ether (0.5 mL, 11.0mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride(100 mg, 85%) as a white solid. MS (M+1) 228.1. ¹H NMR (DMSO-d₆) δ 1.06(t, J=6.93 Hz, 1H) 1.58 (t, J=5.08 Hz, 1H) 2.03-2.19 (m, 1H) 3.16-3.28(m, 1H) 3.47 (dd, J=11.42, 5.95 Hz, 1H) 3.68 (dd, J=11.13, 5.86 Hz, 1H)3.76 (s, 1H) 7.29 (dd, J=10.64, 7.91 Hz, 1H) 7.47-7.81 (m, 3H) 8.08 (d,J=8.00 Hz, 1H) 8.15 (d, J=8.40 Hz, 1H). ¹³C NMR (DMSO-d₆) δ 22.77,30.27, 47.72, 51.66, 109.93, 121.39, 123.69, 125.06, 127.40, 128.44,131.58, 134.08.

A stirred solution/suspension of1-(1-naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (500 mg, 2.4 mmol) in1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde(1.2 mL, 24 mmol), then with sodium triacetoxyborohydride (2.5 g, 12mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL).The organic layer was separated and the aqueous solution was extractedwith methylene chloride containing 2-propanol (2×10 mL). The combinedorganic solution was dried (MgSO₄) and concentrated in vacuo to afford3-methyl-1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (76 mg, 84%,essentially pure without chromatography). This was dissolved inanhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford3-methyl-1-(naphthalen-1-yl)-3-azabicyclo[3.1.0]hexane, hydrochloride(72 mg, 82%) as a white solid. MS (M+1) 224.1. ¹H NMR (DMSO-d₆) δ 0.97(dd, J=7.71, 6.54 Hz, 1H) 1.97-2.10 (m, 1H) 2.14-2.24 (m, 1H) 2.77-2.81(m, J=4.69, 4.69 Hz, 3H) 3.20-3.31 (m, 1H) 3.67-3.76 (m, 2H) 3.94 (dd,J=11.13, 5.08 Hz, 1H) 7.47 (dd, J=8.20, 7.03 Hz, 1H) 7.51-7.58 (m, 1H)7.59-7.66 (m, 2H) 7.88 (d, J=8.20 Hz, 1H) 7.95 (d, J=7.61 Hz, 1H) 8.15(d, J=8.40 Hz, 1H); ¹³C(DMSO-d₆) δ 14.53, 22.27, 30.45, 56.77, 60.55,124.71, 126.25, 126.65, 127.30, 128.31, 128.94, 129.41, 132.98, 134.02,134.97

A stirred solution/suspension of1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (215 mg, 0.95mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueousformaldehyde (0.5 mL, 9.5 mmol), then with sodium triacetoxyborohydride(1.25 g, 4.75 mmol), stirred for 3 h, then treated with 1N sodiumhydroxide (5 mL). The organic layer was separated and the aqueoussolution was extracted with methylene chloride containing a little2-propanol (2×10 mL). The combined organic solution was dried (MgSO₄)and concentrated in vacuo to afford1-(4-fluoronaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (150 mg,65%, essentially pure without chromatography). This was dissolved inanhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford3-methyl-1-(4-fluoronaphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane,hydrochloride (150 mg, 82%) as a white solid. MS (M+1) 242.1. ¹H NMR(DMSO-d₆) δ 0.91-1.01 (m, 1H) 2.01-2.09 (m, 1H) 2.13-2.24 (m, 1H)2.72-2.84 (m, J=4.69 Hz, 3H) 3.16-3.30 (m, 1H) 3.72 (q, J=5.60 Hz, 2H)3.93 (dd, J=11.23, 5.17 Hz, 1H) 7.31 (dd, J=10.74, 8.01 Hz, 1H)7.48-7.79 (m, 3H) 8.07 (d, J=8.20 Hz, 1H) 8.20 (d, J=8.40 Hz, 1H).¹³C(DMSO-d₆) δ 14.51, 22.36, 29.97, 56.72, 60.47, 109.90, 121.34,123.61, 125.04, 127.43, 128.50, 131.39, 134.24 157.08.

A stirred solution/suspension of1-(4-methylnaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (85 mg, 0.38 mmol)in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde(0.23 mL, 3.0 mmol), then with sodium triacetoxyborohydride (318 mg, 1.5mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL).The organic layer was separated and the aqueous solution was extractedwith methylene chloride containing 2-propanol (2×10 mL). The combinedorganic solution was dried (MgSO₄) and concentrated in vacuo to afford1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (76 mg,84%, essentially pure without chromatography). This was dissolved inanhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7mmol), stirred a few minutes, filtered, rinsed with ether, collected,and dried in vacuo to afford1-(4-methylnaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane,hydrochloride (72 mg, 82%) as a white solid. MS (M+1) 238.1. ¹H NMR(CDCl₃) δ 12.70 (br s, 1H), 8.16 (m, 1H), 8.04 (m, 1H), 7.58 (m, 2H),7.37 (m, 1H), 7.26 (m, 1H), 4.20 (m, 1H), 4.06 (m, 1H), 3.50 (m, 1H),3.14 (m, 1H), 2.90 (d, 3H, J=5 Hz), 2.68 (s, 3H), 2.40 (m, 1H), 2.13 (m,1H), 1.22 (m, 1H). ¹³C NMR (CDCl₃) δ 135.73, 133.21, 131.70, 126.81,126.35, 126.33, 125.41, 124.54, 61.65, 57.62, 41.52, 30.97, 22.37,19.75.

EXAMPLE XIV Preparation of 1-Aryl-3-aza-bicyclo[3.1.0]hexane and1-Aryl-3-methyl-3-aza-bicyclo[3.1.0]hexane Using Reaction Schemes 5,6and 13

To a stirring solution of 1-naphthylacetonitrile (15 g, 0.090 moles) inanhydrous THF (150 mL) at −15 to −10° C. under nitrogen, was added 90 mLof sodium bis(trimethylsilyl)amide (NaHMDS, 1M in THF) slowly viaaddition funnel while keeping the temperature below −5° C. The resultingbrown mixture was stirred for 0.75 h between −10° C. and 0° C.R-epichlorohydrin (8.3 g, 0.090 moles in 10 mL of THF) was added slowlyover 15 minutes while keeping the temperature below −10° C. The mixturewas stirred between −10° C. and 0° C. for 0.5 h then NaHMDS (90 mL,0.090 moles) was added while keeping the temperature between −10° C. and−15° C. The mixture was stirred for 45 minutes then warmed to roomtemperature, stirred 30 min and quenched with 40 mL of water. Themixture was stirred 5 minutes, allowed to settle and the layers wereseparated. The lower aqueous layer was re-extracted with EtOAc (˜75 mL).The organics were combined, washed with 100 mL of saturated NaCl, driedover Na₂SO₄, filtered and concentrated to provide an oil. Chromatographythrough a short silica gel plug eluting with EtOAc/Heptane (5-50%)afforded 6.8 g of product. ¹H NMR shows a mixture of diastereomers (˜3:1cis/trans). The product was carried forward to reduction without furthercharacterization. ¹H NMR (400 MHz, CDCl₃, partial assignment) δ1.53-1.66 (m, 2H), 1.85-1.95 (m, 1H), 3.18 (br. s., 1H), 3.85-3.96 (m,1H), 4.13-4.22 (m, 1H), 7.31-7.39 (m, 1H), 7.43-7.55 (m, 2H), 7.57-7.65(m, 1H), 7.78-7.91 (m, 2H), 8.46-8.54 (m, 1H).

Yield=34%; ¹H NMR (400 MHz, CDCl₃, partial assignment) δ 1.53-1.66 (m,2H), 1.85-1.95 (m, 1H), 3.18 (br. s., 1H), 3.85-3.96 (m, 1H), 4.13-4.22(m, 1H), 7.31-7.39 (m, 1H), 7.43-7.55 (m, 2H), 7.57-7.65 (m, 1H),7.78-7.91 (m, 2H), 8.46-8.54 (m, 1H).

Yield=63%; ¹H NMR (400 MHz, CDCl₃, partial assignment) δ 1.59-1.66 (m,1H), 1.68-1.74 (m, 1H), 1.98-2.07 (m, 1H), 2.41 (br. s., 1H), 3.85 (dd,J=12.10, 8.30 Hz, 1H), 4.07-4.13 (m, 1H), 7.33 (dd, J=8.49, 2.05 Hz,1H), 7.45-7.53 (m, 2H), 7.77-7.87(m, 4H).

Yield=56%; ¹H NMR (400 MHz, CDCl₃) δ 1.64-1.73 (m, 3H), 1.94-2.07 (m,2H), 3.97 (dd, J=11.91, 8.69 Hz, 1H), 4.28 (dd, J=11.91, 5.08 Hz, 1H),7.39-7.45 (m, 1H), 7.48-7.59 (m, 2H), 7.62-7.68 (m, 1H), 7.88 (dd,J=15.18, 8.15 Hz, 2H), 8.48 (dd, J=8.49, 0.78 Hz, 1H).

Yield=not isolated; ¹H NMR (400 MHz, CDCl₃, partial assignment) δ 1.44(dd, J=6.98, 6.00 Hz, 1H), 1.72 (dd, J=9.42, 5.91 Hz, 1H), 1.83-1.93 (m,1H), 2.19-2.44 (m, 4H), 3.77 (dd, J=12.10, 8.30 Hz, 1H), 4.00-4.08 (m,1H), 6.88-7.01 (m, 2H), 7.08-7.21 (m, 1H).

Yield=40%; ¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.13 Hz, 1H), 1.56 (d,J=8.10 Hz, 1H), 1.83-1.92 (m, 1H), 2.23 (d, J=1.76 Hz, 3H), 2.46 (br.s., 1H), 3.76 (dd, J=12.06, 8.25 Hz, 1H), 4.03 (dd, J=12.10, 5.17 Hz,1H), 6.92 (dd, J=10.54, 1.85 Hz, 1H), 6.98 (dd, J=7.91, 1.95 Hz, 1H),7.02-7.21 (m, 1H).

To a stirring solution of 4-chloro-3-trifluoromethylphenylacetonitrile(11 g, 0.050 moles) in anhydrous THF (100 mL) at −18° C. under nitrogen,was added 1.95 g (0.050 mmoles 1 eq) of sodium amide in one portion. Theresulting mixture was stirred for 1 h between −15° C. and −5° C. Thedark mixture was cooled to −15° C. and R-epichlorohydrin (4.6 g, 0.050moles in 10 mL of THF) was added slowly over 15 minutes while keepingthe temperature below −10° C. The mixture was stirred between −15° C.and −5° C. for 0.75 h then cooled to −15° C. and another 1 equivalent(1.95 g) of sodium amide was added in one portion. The mixture wasstirred for 3.5 h while allowing to warm to between −10 and +5° C. thenallowed to warm to room temperature and quenched with 50 mL of saturatedNH₄Cl. The mixture was stirred 5 minutes, allowed to settle and thelayers were separated. The lower aqueous layer was re-extracted withEtOAc (2×50 mL). The organics were combined, washed with 100 mL ofsaturated NaCl, dried over Na₂SO₄, filtered and concentrated to a darkoil. Chromatography through a short silica gel plug eluting withEtOAc/Heptane (5-35%) afforded 5.5 g (40%) of product as a dark red oil.¹H NMR shows a mixture of diastereomers. ¹H NMR (400 MHz, CDCl₃) δ1.42-1.52 (m, 1H), 1.59-1.72 (m, 1H), 1.89-1.99 (m, 1H), 2.08 (br. s.,1H), 3.79 (dd, J=12.08, 8.33 Hz, 1H), 4.12 (dd, J=12.13, 4.90 Hz, 1H),7.42-7.55 (m, 1H), 7.56-7.63 (m, 1H), 7.67-7.76 (m, 1H).

Yield=60%; ¹H NMR (400 MHz, CDCl₃) δ 1.42-1.52 (m, 1H), 1.59-1.72 (m,1H), 1.89-1.99 (m, 1H), 2.08 (br. s., 1H), 3.79 (dd, J=12.08, 8.33 Hz,1H), 4.12 (dd, J=12.13, 4.90 Hz, 1H), 7.42-7.55 (m, 1H), 7.56-7.63 (m,1H), 7.67-7.76 (m, 1H).

Yield=41%; ¹H NMR (400 MHz, CDCl₃) δ 1.57-1.65 (m, 2H), 1.84-1.95 (m,1H), 2.61 (q, J=5.27 Hz, 1H), 3.68-3.78 (m, 1H), 4.01-4.11 (m, 1H),7.02-7.10 (m, 1H), 7.29-7.40 (m, 1H).

Yield=39%; ¹H NMR (400 MHz, CDCl₃) δ 1.55-1.65 (m, 2H), 1.84-1.95 (m,1H), 2.61 (q, J=5.27 Hz, 1H), 3.68-3.78 (m, 1H), 4.01-4.11 (m, 1H),7.00-7.10 (m, 1H), 7.31-7.40 (m, 1H).

Yield=20%; ¹H NMR (400 MHz, CDCl₃) δ 1.36-1.46 (m, 1H), 1.55-1.64 (m,1H), 1.84-1.94 (m, 1H), 2.07-2.20 (m, 1H), 3.76 (dd, J=12.10, 8.40 Hz,1H), 4.05-4.12 (m, 1H), 7.10-7.15 (m, 1H), 7.17-7.23 (m, 1H), 7.33-7.37(m, 1H)

Yield=34%; ¹H NMR (400 MHz, CDCl₃) δ 1.37-1.46 (m, 1H), 1.54-1.65 (m,1H), 1.77 (dd, J=9.47, 5.95 Hz, 1H), 1.83-1.95 (m, 1H), 3.76 (dd,J=12.10, 8.40 Hz, 1H), 4.06-4.13 (m, 1H), 7.12-7.16 (m, 1H), 7.17-7.22(m, 1H), 7.33-7.38 (m, 1H).

To a stirring slurry of lithium aluminum hydride (LAH), (2.31 g, 0.061moles) in THF (30 mL) at 0-5° C. was added a solution of crude nitrile,A(1) (6.8 g, (0.030 moles) in 80 mL of THF), slowly via addition funnelwhile keeping the temperature below 10° C. The mixture was stirred for45 minutes while warming to −15° C., after which time, no startingmaterial was observed by TLC analysis (SiO₂ plate, EtOAc/Heptane 1:1).The reaction was carefully quenched by the dropwise addition of H₂O (2.5mL) followed by 2.5 mL of 15% NaOH and lastly 8 mL of H₂O. The resultingoff white slurry was stirred for 1 h then filtered through a Celite pad,washing with 2×50 mL of EtOAc. The filtrate was concentrated to a paleyellow oil. Chromatography on silica gel eluting with CH₂Cl₂MeOH/NH₄OH(20:1:0.1 to 10:1:0.1) afforded 3.3 g (47%) of pure amino alcohol as alight brown colored oil. ¹H NMR (400 MHz, CDCl₃) δ 1.01-1.09 (m, J=5.22,5.22 Hz, 1H), 1.15 (dd, J=8.64, 4.93 Hz, 1H), 1.70 (br. s., 1H),1.77-1.89 (m, 1H), 2.52 (br. s., 1H), 3.34-3.56 (m, J=11.52, 11.52 Hz,2H), 3.58-3.69 (m, 1H), 4.17-4.30 (m, J=11.23 Hz, 2H), 7.39-7.55 (m,3H), 7.56-7.62 (m, 1H), 7.77 (d, J=8.20 Hz, 1H), 7.84-7.91 (m, 1H), 8.28(br. s., 1H).

Yield=47%; ¹H NMR (400 MHz, CDCl₃) δ 1.00-1.09 (m, 1H) 1.13 (dd, J=8.59,4.78 Hz, 1H) 1.81-1.93 (m, 1H) 2.61-3.05 (m, 4H) 3.41-3.51 (m, 1H)3.55-3.64 (m, 1H) 4.17-4.28 (m, 1H) 7.39-7.57 (m, 3H) 7.65 (d, J=6.93Hz, 1H) 7.73-7.80 (m, 1H) 7.85-7.91 (m, 1H) 8.30 (br. s., 1H).

Yield=56%; ¹H NMR (400 MHz, CDCl₃) δ 0.79-0.79 (m, 1H), 1.03 (dd,J=8.59, 4.78 Hz, 1H), 1.83-1.93 (m, 1H), 2.54 (br. s., 3H), 2.64 (d,J=12.59 Hz, 1H), 3.40 (dd, J=12.15, 11.08 Hz, 1H), 3.53 (dd, J=12.59,0.78 Hz, 1H), 4.17 (dd, J=12.20, 5.47 Hz, 1H), 7.41-7.54 (m, 3H),7.77-7.83 (m, 3H), 7.85 (d, J=1.37 Hz, 1H).

Yield=55%; ¹H NMR (400 MHz, CDCl₃) δ 0.80 (t, J=5.12 Hz, 1H), 0.82 (m,1H), 1.03 (dd, J=8.59, 4.78 Hz, 1H), 1.82-1.94 (m, 1H), 2.47-2.70 (m,J=12.59 Hz, 4H), 3.40 (dd, J=12.15, 11.08 Hz, 1H), 3.53 (dd, J=12.59,0.78 Hz, 1H), 4.17 (dd, J=12.20, 5.47 Hz, 1H), 7.41-7.54 (m, 3H),7.77-7.84 (m, 3H), 7.85 (d, J=1.37 Hz, 1H).

Yield=38%; ¹H NMR (400 MHz, CDCl₃) δ 0.67-0.75 (m, J=5.17, 5.17 Hz, 1H),0.93 (dd, J=8.59, 4.78 Hz, 1H), 1.66-1.77 (m, 1H), 2.23 (d, J=1.85 Hz,3H), 2.56 (d, J=12.59 Hz, 1H), 2.95 (br. s., 3H), 3.32 (dd, J=12.25,10.98 Hz, 1H), 3.43 (dd, J=12.54, 0.83 Hz, 1H), 4.10 (dd, J=12.30, 5.47Hz, 1H), 6.99-7.15 (m, 3H).

Yield=43%; ¹H NMR (400 MHz, CDCl₃) δ 0.72 (t, J=5.17 Hz, 1H), 0.93 (dd,J=8.59, 4.78 Hz, 1H), 1.65-1.77 (m, 1H), 2.23 (d, J=1.85 Hz, 3H), 2.56(d, J=12.59 Hz, 1H), 2.95 (br. s., 3H), 3.32 (dd, J=12.25, 10.98 Hz,1H), 3.43 (dd, J=12.54, 0.83 Hz, 1H), 4.10 (dd, J=12.30, 5.47 Hz, 1H),6.95-7.17 (m, 3H).

To a stirring solution of(1S,2R)-2-Hydroxymethyl-1-(4-chloro-3-trifluoromethylphenyl)cyclopropancarbonitrileprepared according to Example XIV.A (7) above (5.5 g mg, 20 mmoles) inTHF (75 mL) at room temperature under nitrogen was added 29.9 mL (60mmoles) of BH₃.Me₂S (2M in THF). The reaction flask was fitted with aDean Stark trap and the mixture was heated to a gentle reflux. Themixture was refluxed for 3 h while distilling out solvent and Me₂S(about 20-25 mL was collected). No starting nitrile was observed by TLCanalysis (SiO₂ plate, EtOAc/Heptane 1:1). The mixture was cooled to roomtemperature and carefully quenched with MeOH (10 mL) then added 20 mL of6N HCl and refluxed for 0.5 h. The mixture was cooled to roomtemperature, basified with solid K₂CO₃. The resulting slurry was dilutedwith EtOAc (75 mL), filtered and concentrated to a pale yellow oil.Chromatography on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH (50:1:0.1 to10:1:0.1) afforded 2.35 g (42%) of the pure amino alcohol as a paleyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 0.72-0.84 (m, 1H), 0.87-0.99 (m,J=7.86, 4.44 Hz, 1H), 1.57-1.78 (m, J=21.57 Hz, 2H), 2.60 (d, J=12.98Hz, 1H), 2.92 (s, 3H), 3.24-3.48 (m, 2H), 3.53-3.71 (m, J=3.61 Hz, 1H),4.02-4.17 (m, 1H), 7.37-7.55 (m, 2H), 7.66 (s, 1H).

Yield=35%; ¹H NMR (400 MHz, CDCl₃) δ 0.80 (t, J=5.31 Hz, 1H), 0.94 (dd,J=8.69, 5.03 Hz, 1H), 1.61-1.77 (m, 1H), 2.61 (d, J=12.90 Hz, 1H), 2.83(br. s., 3H), 3.33 (dd, J=12.26, 10.98 Hz, 1H), 3.38-3.46 (m, 1H), 4.10(dd, J=12.31, 5.35 Hz, 1H), 7.40-7.46 (m, 1H), 7.47-7.53 (m, 1H), 7.67(d, J=2.01 Hz, 1H).

Yield=56%; ¹H NMR (400 MHz, CDCl₃) δ 0.73-0.79 (m, 1H), 0.94 (dd,J=8.71, 5.01 Hz, 1H), 1.65-1.77 (m, 1H), 2.54-2.62 (m, J=12.69 Hz, 1H),2.78 (d, J=10.74 Hz, 3H), 3.32 (dd, J=12.30, 10.93 Hz, 1H), 3.40-3.48(m, 1H), 4.10 (dd, J=12.40, 5.37 Hz, 1H), 7.09-7.20 (m, 2H), 7.28-7.36(m, 1H).

Yield=37%; ¹H NMR (400 MHz, CDCl₃) δ 0.74-0.80 (m, 1H), 0.95 (dd,J=8.69, 4.98 Hz, 1H), 1.66-1.78 (m, 1H), 2.01 (br. s., J=74.09 Hz, 3H),2.59 (d, J=12.69 Hz, 1H), 3.33 (dd, J=12.30, 10.93 Hz, 1H), 3.44 (dd,J=12.74, 0.93 Hz, 1H), 4.11 (dd, J=12.35, 5.42 Hz, 1H), 7.11-7.15 (m,1H), 7.18 (dd, J=10.01, 2.00 Hz, 1H), 7.33 (t, J=7.96 Hz, 1H).

Yield=47%; ¹H NMR (400 MHz, CDCl₃) δ 0.74 (t, J=5.22 Hz, 1H), 0.93 (dd,J=8.69, 4.88 Hz, 1H), 1.61-1.75 (m, 1H), 2.57 (d, J=12.79 Hz, 1H), 2.72(br. s., 3H), 3.31 (dd, J=12.30, 10.93 Hz, 1H), 3.39 (dd, J=12.79, 0.98Hz, 1H), 4.10 (dd, J=12.30, 5.37 Hz, 1H), 7.07 (t, J=8.69 Hz, 1H),7.22-7.29 (m, 1H), 7.43 (dd, J=7.08, 2.20 Hz, 1H).

Yield=55%; ¹H NMR (400 MHz, CDCl₃) δ 0.75 (m, 1H), 0.93 (dd, J=8.69,4.88 Hz, 1H), 1.61-1.75 (m, 1H), 2.59 (d, J=12.79 Hz, 1H), 2.74 (br. s.,3H), 3.31 (dd, J=12.30, 10.93 Hz, 1H), 3.39 (dd, J=12.79, 0.98 Hz, 1H),4.10 (dd, J=12.30, 5.37 Hz, 1H), 7.07 (t, J=8.69 Hz, 1H), 7.23-7.28 (m,1H), 7.45 (dd, J=7.08, 2.20 Hz, 1H).

To a stirring solution of(1R,2S)-(2-Aminomethyl-2-(1-naphthyl)cyclopropyl)-methanol preparedaccording to Example XIVB(1) above (3.2 g, 0.014 moles) in 35 mL ofdichloroethane (DCE), at room temperature under nitrogen, was added 1.2mL (0.017 moles, 1.2 eq) of SOCl₂ slowly via syringe while keeping thetemperature below 50° C. (Note: The reaction exotherms from 22° C. to45° C.) The resulting mixture was stirred for 3.5 h at room temperatureafter which time, TLC analysis (SiO₂ plate, CH₂Cl₂/MeOH/NH₄OH(10:1:0.1)) showed no starting material remaining. The mixture wasquenched with 40 mL of water and the layers were separated. The organiclayer was washed with H₂O (2×50 mL). The aqueous layers were combined,made basic with 10N NaOH to pH=10 (pH paper) and extracted with 2×100 mLof CH₂Cl₂. The combined organics were dried over Na₂SO₄, filtered andconcentrated to an oil. The oil was dissolved in MeOH (20 mL), treatedwith 15 mL of 2M HCl/Et₂O and concentrated in vacuo to a suspension. Theslurry was diluted with 25 mL of Et₂O, filtered and washed with 35 mL ofEt₂O. The solid product was dried overnight (˜29 mmHg, 50° C.) to give 1g (29%) of pure product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.22(t, J=7.37 Hz, 1H), 1.58 (dd, J=6.00, 4.73 Hz, 1H), 2.03-2.10 (m, 1H),3.25-3.27 (m, 1H), 3.42 (d, J=11.52 Hz, 1H), 3.64 (d, J=11.62 Hz, 1H),3.74-3.85 (m, 2H), 7.32-7.39 (m, 1H), 7.40-7.48 (m, 2H), 7.48-7.55 (m,1H), 7.75 (d, J=8.20 Hz, 1H), 7.79-7.85 (m, 1H), 8.04 (d, J=8.30 Hz,1H), ¹³C NMR (101 MHz, CDCl₃) δ 14.54, 22.43, 30.89, 48.01, 51.89,123.92, 125.60, 126.24, 126.93, 129.04, 129.17, 133.55, 134.04, LC/MS(m/z M⁺¹) 210.0, [α]_(D) (c=1, MeOH), =−54.4.

Yield=29%; ¹H NMR (400 MHz, METHANOL-d₄) δ 1.24-1.32 (m, 1H), 1.32-1.37(m, 1H), 2.23-2.31 (m, 1H), 3.47 (d, J=11.71 Hz, 1H), 3.66 (d, J=11.71Hz, 1H), 3.85 (d, J=11.62 Hz, 1H), 3.93 (dd, J=11.67, 3.95 Hz, 1H), 7.46(dd, J=8.25, 7.08 Hz, 1H), 7.50-7.57 (m, 1H), 7.57-7.65 (m, 2H), 7.86(d, J=8.30 Hz, 1H), 7.89-7.95 (m, 1H), 8.17 (d, J=8.49 Hz, 1H), ¹³C NMR(101 MHz, METHANOL-d₄) δ 22.36, 30.65, 30.65, 48.09, 51.99, 123.78,125.47, 125.89, 126.50, 128.65, 128.88, 133.87, 134.28, LC/MS (m/z M⁺¹210.0), [α]_(D) (c=1, MeOH), =+55.6.

Yield=32%; ¹H NMR (400 MHz, CDCl₃) δ 1.33-1.40 (m, J=7.52, 7.52 Hz, 1H),1.67 (dd, J=6.64, 4.69 Hz, 1H), 2.03-2.11 (m, 1H), 3.63-3.80 (m, 3H),3.85-3.94 (m, J=11.23, 5.95 Hz, 1H), 7.23-7.29 (m, 1H), 7.43-7.52 (m,2H), 7.66 (d, J=1.56 Hz, 1H), 7.75-7.83 (m, 3H), 9.81-9.98 (m, J=7.81Hz, 1H), 10.38 (s, 1H), ¹³C NMR (101 MHz, CDCl₃) δ 15.56, 23.47, 31.79,47.87, 50.99, 125.01, 126.38, 126.42, 126.84, 127.78, 127.86, 128.95,132.67, 133.46, 135.50, LC/MS (m/z M⁺¹ 210.1), [α]_(D) (c=1, MeOH),=−82.2.

Yield=30%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.14-1.23 (m, 1H), 1.44-1.50 (m,1H), 2.17-2.26 (m, 1H), 3.36-3.43 (m, 1H), 3.47-3.61 (m, 2H), 3.75 (d,J=11.23 Hz, 1H), 7.36 (dd, J=8.59, 1.85 Hz, 1H), 7.42-7.53 (m, 2H), 7.80(d, J=1.56 Hz, 1H), 7.82-7.90 (m, 3H), 9.76 (br. s., 1H), ¹³C NMR (101MHz, DMSO-d₆) δ 16.41, 24.11, 31.36, 47.50, 49.97, 125.43, 125.76,126.41, 127.04, 128.07, 128.15, 128.74, 132.39, 133.55, 137.62), LC/MS(m/z M⁺¹ 210.1, [α]_(D) (c=1, MeOH), =+66.0.

Yield=64%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.99-1.08 (m, 1H), 1.39-1.45 (m,1H), 2.05-2.13 (m, 1H), 2.17 (d, J=1.37 Hz, 3H), 3.28-3.35 (m, 1H),3.35-3.48 (m, 2H), 3.63 (d, J=10.64 Hz, 1H), 6.97 (dd, J=7.81, 1.76 Hz,1H), 7.05 (dd, J=11.32, 1.76 Hz, 1H), 7.19 (t, J=8.10 Hz, 1H), 9.70 (br.s., 1H), 9.96 (br. s., 2H), ¹³C NMR (101 MHz, DMSO-d₆) δ 14.43 (d,J=3.16 Hz) 16.59, 24.15, 30.72 (d, J=2.01 Hz) 47.30, 49.70, 113.87 (d,J=22.92 Hz) 122.91 123.01, 132.18 (d, J=5.66 Hz) 140.21 (d, J=7.86 Hz)161.31 (d, J=242.57 Hz), LC/MS (m/z M⁺¹ 192.1), [α]_(D) (c=1, MeOH),=−58.4.

Yield=95% * crude; ¹H NMR (400 MHz, DMSO-d₆) δ 1.00-1.09 (m, 1H),1.36-1.44 (m, 1H), 2.05-2.14 (m, 1H), 2.17 (d, J=1.46 Hz, 3H), 3.32 (d,J=11.13 Hz, 1H), 3.37-3.47 (m, 2H), 3.63 (d, J=11.13 Hz, 1H), 6.97 (dd,J=7.81, 1.85 Hz, 1H), 7.05 (dd, J=11.32, 1.76 Hz, 1H), 7.20 (t, J=8.15Hz, 1H), 9.74 (br. s., 2H), ¹³C NMR (101 MHz, DMSO-d₆) δ 14.44 (d,J=3.16 Hz), 16.54, 24.13, 30.71 (d, J=2.11 Hz, 1 C) 47.34, 49.73, 113.89(d, J=22.91 Hz) 122.92 (d, J=13.90 Hz), 123.03, 132.19 (d, J=5.75 Hz),140.19 (d, J=7.86 Hz), 161.32 (d, J=242.47 Hz), LC/MS (m/z M⁺¹ 192.1),[α]_(D) (c=1, MeOH), =+55.8

To a stirring solution of(1R,2S)-(2-aminomethyl-2-(4-chloro-3-trifluoromethylphenyl)cyclopropyl)-methanolprepared according to Example XIV B(7) above (2.35 g, 8.4 mmoles) in 50mL of dichloroethane (DCE), at room temperature under nitrogen, wasadded 0.8 mL (10.1 mmoles, 1.3 eq) of SOCl₂ slowly via syringe whilekeeping the temperature below 40° C. The resulting mixture was stirredfor 2 h at room temperature after which time, TLC analysis (SiO₂ plate,CH₂Cl₂/MeOH/NH₄OH (10:1:0.1)) showed remaining no starting material. Themixture was quenched with 125 mL of water, diluted with CH₂Cl₂ (75 mL)stirred 2-3 minutes, allowed to settle and the layers were separated.The organic layer was washed with H₂O (75 mL). The aqueous layers werecombined, made basic with 10N NaOH to pH=10 (pH paper) and extractedwith 2×100 mL of CH₂Cl₂. The combined organics were dried over Na₂SO₄,filtered and concentrated to an oil. The oil was dissolved in MeOH (40mL), treated with 20 mL of 2M HCl/Et₂O, concentrated to ˜5-10 mL totalvolume and then diluted with 30 mL of Et₂O and 5 mL of heptane. Theresulting slurry was filtered and washed with 35 mL of cold Et₂O. Thesolid product was dried overnight (˜29 mmHg, 50° C.) to give 1.8 g (72%)of pure product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.01-1.07(m, 1H), 1.13-1.18 (m, 1H), 1.77-1.85 (m, 1H), 3.19-3.33 (m, 3H), 3.42(d, J=11.13 Hz, 1H), 5.10 (br.s, 2H), 7.29 (dd, J=8.20, 2.15 Hz, 1H),7.42 (d, J=8.40 Hz, 1H), 7.47 (d, J=2.34 Hz, 1H); ¹³C NMR (101 MHz,CDCl₃) δ 15.81, 23.59, 31.02, 47.75, 50.68, 121.35, 124.07, 126.38,129.14 (d, J=31.45 Hz), 131.63 (d, J=1.72 Hz), 131.94 (d, J=0.96 Hz),132.21, 137.50, LC/MS (m/z M⁺¹ 262.0), [α]_(D) (c=1, MeOH), =−54.2.

Yield=43%; ¹H NMR (400 MHz, CDCl₃) δ 1.17-1.26 (m, 1H), 2.03-2.11 (m,J=6.64 Hz, 1H), 2.30-2.38 (m, J=6.30, 4.44 Hz, 1H), 2.87-2.98 (m, J=2.15Hz, 3H), 3.20-3.29 (m, 1H), 3.31-3.41 (m, 1H), 3.89-4.00 (m, 1H),4.09-4.18 (m, 1H), 7.28-7.35 (m, 1H), 7.44-7.52 (m, 2H), 12.78 (br. s.,1H); ¹³C NMR (101 MHz, CDCl₃) δ 15.95, 23.64, 31.02, 47.75, 50.68,121.35, 124.07, 126.51, 129.12 (d, J=31.45 Hz), 131.62 (d, J=1.72 Hz),131.96 (d, J=0.96 Hz), 132.21, 137.50, LC/MS (m/z M⁺¹262.0), [α]_(D)(c=1, MeOH), =+58.3.

Yield=68%; ¹H NMR (400 MHz, CDCl₃) δ 1.16-1.27 (m, J=7.52, 7.52 Hz, 1H),1.58-1.69 (m, 1H), 1.91-2.04 (m, 1H), 3.49-3.69 (m, J=5.47 Hz, 3H),3.72-3.83 (m, J=11.03, 5.76 Hz, 1H), 6.87-7.01 (m, 2H), 7.34 (t, J=7.91Hz, 1H), 9.86 (s, 1H), 10.32 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 16.14,23.91, 30.99 (d, J=1.82 Hz), 47.67, 50.55, 115.67 (d, J=21.76 Hz),120.32 (d, J=17.55 Hz), 123.72 (d, J=3.64 Hz), 131.25, 139.17 (d, J=6.71Hz) 158.35 (d, J=250.24 Hz), LC/MS (m/z M⁺¹ 212.0), [α]_(D) (c=1, MeOH),=−76.0.

Yield=31%; ¹H NMR (400 MHz, METHANOL-d₄) δ 1.20 (dd, J=6.54, 4.90 Hz,1H), 1.26-1.32 (m, 1H), 2.17-2.24 (m, 1H), 3.51 (d, J=11.53 Hz, 1H),3.59-3.71 (m, 2H), 3.76 (d, J=11.35 Hz, 1H), 7.09-7.15 (m, 1H), 7.23(dd, J=10.48, 2.15 Hz, 1H), 7.43 (t, J=8.05 Hz, 1H); ¹³C NMR (101 MHz,METHANOL-d₄) δ 15.34, 23.74, 30.60 (d, J=1.92 Hz), 50.31, 115.43 (d,J=22.05 Hz), 119.25 (d, J=17.74 Hz), 123.90 (d, J=3.55 Hz), 130.79,140.30 (d, J=7.09 Hz), 158.16 (d, J=247.84 Hz), LC/MS (m/z M⁺¹ 212.0),[α]_(D) (c=1, MeOH), =+64.0.

Yield=34%; ¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.42 Hz, 1H), 1.59 (dd,J=6.64, 4.88 Hz, 1H), 1.91-1.99 (m, 1H), 3.45-3.68 (m, 3H), 3.75 (dd,J=11.23, 6.15 Hz, 1H), 7.05-7.14 (m, 2H), 7.21-7.27 (m, 1H), 9.84 (s,1H), 10.32 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 15.62, 23.53, 30.92,47.76, 50.99, 117.20 (d, J=21.29 Hz), 121.63 (d, J=18.03 Hz), 127.46 (d,J=7.29 Hz), 129.99, 135.29 (d, J=3.93 Hz), 157.58 (d, J=249.76 Hz),LC/MS (m/z M⁺¹ 212.1); [α]_(D) (c=1, MeOH), =−42.8.

Yield=59%; ¹H NMR (400 MHz, CDCl₃) δ 1.15-1.24 (m, 1H), 1.60 (dd,J=6.54, 4.78 Hz, 1H), 1.90-1.97 (m, 1H), 3.47-3.69 (m, 3H), 3.74 (dd,J=11.27, 6.10 Hz, 1H), 7.04-7.12 (m, 2H), 7.21-7.26 (m, 1H), 9.81 (br.s., 1H), 10.26 (br. s., 1H); ¹³C NMR (101 MHz, CDCl₃) δ 19.22, 27.40,34.82, 51.77, 54.96, 121.04 (d, J=21.38 Hz), 125.37 (d, J=18.03 Hz),131.53 (d, J=7.29 Hz), 133.94, 139.23 (d, J=3.93 Hz), 161.48 (d,J=249.38 Hz), LC/MS (m/z M⁺¹ 212.1), [α]_(D) (c=1, MeOH), =+41.4.

¹H NMR (400 MHz, CDCl₃) δ 1.22-1.31 (m, 1H), 2.14-2.21 (m, 1H), 2.45 (d,J=6.50 Hz, 1H), 2.91 (d, J=4.76 Hz, 3H), 3.11-3.23 (m, 1H), 3.46-3.55(m, 1H), 4.08 (dd, J=11.07, 5.31 Hz, 1H), 4.19-4.27 (m, 1H), 7.39-7.64(m, 4H), 7.83 (d, J=8.14 Hz, 1H), 7.87-7.93 (m, 1H), 8.11-8.20 (m, 1H),12.85 (br. s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 15.05, 22.11-22.56 (m, 1C) 30.92, 41.35, 57.25-57.70 (m, 1 C) 61.37, 124.02, 125.67, 126.41,127.12, 129.18, 132.72, 133.51, 134.03, LC/MS (m/z M⁺¹ 224.1); [α]_(D)(c=1, MeOH), =−60.6.

Yield=58%; ¹H NMR (400 MHz, DMSO-d₆) δ 0.93-1.03 (m, 1H), 2.01 (br. s.,1H), 2.14-2.25 (m, 1H), 2.79 (s, 3H), 3.19-3.34 (m, 1H), 3.89-4.01 (m,1H), 7.48 (dd, J=8.10, 7.22 Hz, 1H), 7.52-7.58 (m, 1H), 7.59-7.66 (m,2H), 7.88 (d, J=8.20 Hz, 1H), 7.96 (d, J=7.61 Hz, 1H), 8.16 (d, J=8.40Hz, 1H), 11.30 (br. s., 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 14.56, 22.27,30.46, 40.33, 56.83, 60.63, 124.73, 126.25, 126.65, 127.29, 128.92,129.41, 132.98, 134.02, [α]_(D) (c=1, MeOH), =+64.2.

Yield=60%; ¹H NMR (400 MHz, CDCl₃) δ 1.27-1.34 (m, 1H), 2.08-2.15 (m,1H), 2.29 (dd, J=6.88, 4.73 Hz, 1H), 2.92 (d, J=4.69 Hz, 3H), 3.31-3.42(m, 2H), 3.95 (dd, J=11.03, 5.27 Hz, 1H), 4.18 (dd, J=10.84, 5.27 Hz,1H), 7.20-7.27 (m, 1H), 7.43-7.53 (m, 2H), 7.62 (d, J=1.66 Hz, 1H),7.74-7.85 (m, 3H), 12.64 (br. s., 1H); ¹³C NMR (101 MHz, CDCl₃) δ 16.40,23.41, 31.85, 41.48, 57.47, 60.56, 124.70, 126.19, 126.52, 126.99,127.73, 127.90, 129.08, 132.69, 133.43, 135.34, LC/MS (m/z M⁺¹ 224.1,[α]_(D) (c=1, MeOH), =−88.6.

Yield=80%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.14-1.22 (m, 1H), 1.89 (dd,J=5.91, 5.03 Hz, 1H), 2.17-2.24 (m, 1H), 2.81 (d, J=4.49 Hz, 3H),3.45-3.54 (m, 1H), 3.60-3.69 (m, 2H), 3.95 (dd, J=10.88, 5.03 Hz, 1H),7.35-7.53 (m, 3H), 7.76-7.89 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ16.13-16.48 (m, 1 C) 24.17, 31.18, 40.32, 56.68, 58.96-59.19 (m, 1 C)125.38, 125.78, 126.45, 127.08, 128.04, 128.17, 128.73, 132.42, 133.51,137.43, LC/MS (m/z M⁺¹ 210.1), [α]_(D) (c=1, MeOH), =+77.8.

Yield=63%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.01-1.09 (m, 1H) 1.76-1.84 (m,1H) 2.05-2.12 (m, 1H) 2.17 (d, J=1.37 Hz, 3H) 2.76 (d, J=4.20 Hz, 3H)3.38-3.53 (m, 2H) 3.56 (dd, J=10.98, 4.83 Hz, 1H) 3.83 (dd, J=10.93,4.88 Hz, 1H) 6.98 (dd, J=7.86, 1.71 Hz, 1H) 7.08 (dd, J=11.32, 1.56 Hz,1H) 7.19-7.25 (m, 1H) 11.35 (br. s., 1H); ¹³C NMR (101 MHz, DMSO-d₆) δppm 14.44 (d, J=3.1 Hz) 16.22, 24.24, 30.54 (d, J=1.2 Hz) 56.55, 58.86,113.94 (d, J=22.7 Hz) 122.96, 123.19 132.18 (d, J=5.7 Hz) 139.95 (d,J=7.8 Hz) 161.32 (d, J=242.8 Hz), LC/MS (m/z M⁺¹ 206.0), [α]_(D) (c=],MeOH), =−69.6.

Yield=63%; ¹H NMR (400 MHz, DMSO-d₆) δ 1.02-1.10 (m, 1H) 1.68-1.74 (m,1H), 2.05-2.12 (m, 1H), 2.18 (d, J=1.56 Hz, 3H), 2.77 (d, J=4.30 Hz,3H), 3.38-3.52 (m, 2H), 3.58 (dd, J=11.08, 4.83 Hz, 1H), 3.84 (dd,J=10.98, 4.93 Hz, 1H), 6.98 (dd, J=7.81, 1.76 Hz, 1H), 7.08 (dd,J=11.32, 1.66 Hz, 1H), 7.21 (t, J=8.10 Hz, 1H), 11.09 (br. s., 1H); ¹³CNMR (101 MHz, DMSO-d₆) δ 14.45 (d, J=3.16 Hz), 16.22, 24.22, 30.51,40.30, 56.65, 58.94, 113.93 (d, J=22.9 Hz), 123.05 (d, J=3.26 Hz),123.18, 132.19 (d, J=5.6 Hz), 139.90 (d, J=8.0 Hz), 161.32 (d, J=242.5Hz), LC/MS (m/z M⁺¹ 206.1), [α]_(D) (c=J, MeOH), =+48.0.

To a stirring solution of amine hydrochloride (0.8 g, 3 mmoles) in 75 mLof dichloroethane (DCE), at room temperature under nitrogen, was added2.1 mL (28 mmoles, 9.2 eq) of formaldehyde (37%) followed by 2.98 g (14mmoles) of sodium triacetoxyborohydride. The resulting mixture wasstirred for 1-2 h at room temperature after which time, LC/MS analysisshowed one main peak corresponding to the desired product. The mixturewas quenched with 20 mL of 1M NaOH, allowed to settle and the layerswere separated. The aqueous layer was washed with 40 mL of CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to an oil. The oil was dissolved in MeOH (5 mL) and treatedwith an excess of 2M HCl/Et₂O. An additional 15 mL ofEt₂O/acetonitrile/heptane (2:1:1) was added. The resulting suspensionwas cooled to 0-5° C. and filtered, washing the product cake with Et₂O(10 mL). The product was dried overnight (˜29 mmHg, 50° C.) to give 520mg (62%) of pure product as a white solid. ¹H NMR (400 MHz, CDCl₃) δ1.17-1.23 (m, 1H), 2.03-2.09 (m, 1H), 2.33 (dd, J=6.93, 4.78 Hz, 1H),2.92 (d, J=4.59 Hz, 3H), 3.22-3.31 (m, J=9.18 Hz, 1H), 3.34-3.42 (m,1H), 3.92 (dd, J=11.03, 5.27 Hz, 1H), 4.11 (dd, J=10.84, 5.27 Hz, 1H),7.31 (dd, J=8.30, 2.05 Hz, 1H), 7.47 (d, J=8.20 Hz, 1H), 7.51 (d, J=2.05Hz, 1H), 12.74 (br. s., 1H); ¹³C NMR (101 MHz, CDCl₃) δ 15.76-15.97 (m,1 C) 23.64-23.81 (m, 1 C) 30.90-31.04 (m, 1 C) 47.56-47.70 (m, 1 C)50.56-50.72 (m, 1 C) 121.25-121.44 (m, 1 C) 123.97-124.16 (m, 1 C)126.35-126.74 (m, 1 C) 129.01-129.41 (m, 1 C), 131.69, 131.93, 137.42,LC/MS (m/z M⁺¹ 276.0), [α]_(D) (c=1, MeOH), =−60.2

Yield 80%; ¹H NMR (400 MHz, CDCl₃) δ 1.17-1.25 (m, 1H), 2.03-2.10 (m,1H), 2.33 (dd, J=6.98, 4.73 Hz, 1H), 2.92 (d, J=4.69 Hz, 3H), 3.23-3.31(m, 1H), 3.34-3.44 (m, 1H), 3.92 (dd, J=10.98, 5.22 Hz, 1H), 4.11 (dd,J=10.84, 5.27 Hz, 1H), 7.32 (dd, J=8.30, 2.05 Hz, 1H), 7.44-7.55 (m,2H), 12.74 (br. s., 1H); ¹³C NMR (101 MHz, CDCl₃) δ 16.31, 23.59, 31.04,41.35, 57.16, 60.04, 121.34, 124.06, 126.53 (q, J=5.27 Hz), 129.20 (d,J=31.54 Hz), 131.82, 132.01, 132.35 (m), LC/MS (m/z M⁺¹ 276.1), [α]_(D)(c=1, MeOH), =+41.4.

Yield=81%; ¹H NMR (400 MHz, CDCl₃) δ 1.10-1.27 (1H), 1.97-2.07 (m, 1H),2.29 (br. s., 1H), 2.91 (s, 3H), 3.19-3.39 (m, 2H), 3.90 (br. s., 1H),4.02-4.17 (m, 1H), 6.91 (d, J=7.81 Hz, 1H), 7.00 (d, J=9.66 Hz, 1H),7.35 (t, J=7.71 Hz, 1 H); ¹³C NMR (101 MHz, CDCl₃) δ 16.09-17.22 (m, 1C) 23.85, 31.04, 41.65, 57.32, 60.14, 115.67 (d, J=21.8 Hz), 120.48 (d,J=17.5 Hz) 123.72, 131.36, 138.97, 158.37 (d, J=250.3 Hz), LC/MS (m/zM⁺¹ 226.0), [α]_(D) (c=1, MeOH), =−79.8.

Yield=87%; ¹H NMR (400 MHz, METHANOL-d₄) δ 1.27 (t, J=7.71 Hz, 1H), 1.47(dd, J=6.78, 4.83 Hz, 1H), 2.17-2.26 (m, 1H), 2.98 (s, 3H), 3.61 (d,J=11.32 Hz, 1H), 3.80 (d, J=11.32 Hz, 1H), 4.03 (d, J=11.23 Hz, 1H),7.10-7.16 (m, 1H), 7.26 (dd, J=10.45, 2.05 Hz, 1H), 7.43 (t, J=8.10 Hz,1H); ¹³C NMR (101 MHz, METHANOL-d₄) δ 14.25, 15.29, 23.70, 39.83, 57.24,59.59, 115.42 (d, J=22.24 Hz, 1 C) 119.36 (d, J=17.74 Hz, 1 C) 123.87(d, J=3.64 Hz, 1 C) 130.81, 140.03, 158.16 (d, J=247.84 Hz, 1 C), LC/MS(m/z M⁺¹ 226.0), [α]_(D) (c=1, MeOH), =+61.6.

Yield=78%; ¹H NMR (400 MHz, CDCl₃) δ 1.03-1.16 (m, 1H) 1.84-2.01 (m, 2H)2.84(s, 3H) 3.17-3.30 (m, 1H) 3.29-3.41 (m, 1H) 3.80 (d, J=10.84 Hz, 1H)3.97 (d, J=10.84 Hz, 1H) 6.97-7.11 (m, 2H) 7.18-7.29 (m, 1H); ¹³C NMR(101 MHz, CDCl₃) δ 15.88, 18.47, 23.27, 30.72, 40.96, 57.26, 60.30,117.17 (d, J=21.4 Hz), 121.50 (d, J=17.9 Hz), 127.51 (d, J=7.2 Hz),129.90, 134.98 (d, J=3.7 Hz), 157.56 (d, J=249.8 Hz), LC/MS (m/z M⁺¹225.7), [α]_(D) (c=1, MeOH), =−46.2.

Yield 59%; ¹H NMR (400 MHz, CDCl₃) δ 1.14 (t, J=7.81 Hz, 1H) 1.93-2.01(m, 1H) 2.19 (dd, J=6.74, 4.69 Hz, 1H) 2.91 (d, J=4.59 Hz, 3H) 3.23-3.32(m, 1H) 3.37-3.46 (m, 1H) 3.86 (dd, J=10.88, 5.12 Hz, 1H) 4.02 (dd,J=10.84, 5.17 Hz, 1H) 7.06-7.11 (m, 2H) 7.26-7.31 (m, 1H); ¹³C NMR (101MHz, CDCl₃) δ 15.83, 23.43, 30.91, 41.26, 57.23, 60.20-60.54 (m, J=0.6Hz), 117.26 (d, J=21.3 Hz), 121.61 (d, J=18.1 Hz), 127.61 (d, J=7.3 Hz,130.00, 135.14 (d, J=3.9 Hz), 157.61 (d, J=249.9 Hz, 157.63, LC/MS (m/zM⁺¹ 225.9), [α]_(D) (c=1, MeOH), =+60.5.

EXAMPLE XV Preparation of 1-Aryl-4-methyl-3-aza-bicyclo[3.1.0]hexaneUsing Reaction Scheme 21

To an oven-dried, three-necked, 500 mL round-bottomed flask was addedthe compound 3,4-dichlorobenzonitrile and THF with stirring under argon.The solution was cooled to −25° C. in a dry ice/MeCN bath and chargedwith 5.3 g of sodium amide. The resulting yellow suspension becameorange upon stirring and was warmed to ambient temperature over 2 hours.The brown mixture was cooled to −25° C. and epichlorohydrin was addeddrop-wise over 10 minutes followed by a second equivalent of sodiumamide in one portion. The golden brown mixture was stirred at −25° C.and warmed to 15° C. over 8 h. The dark red-colored mixture was poured(with stirring) into 500 mL of saturated ammonium chloride. The organicphase was separated and dried over magnesium sulfate for 12 h. Themixture was filtered and concentrated under reduced pressure and driedto afford 31 g of red oil. Half of the material was loaded onto a silicagel (250 g) column and eluted first with hexane. Later the polarity wasincreased to 10% EtOAc in hexanes and finally to 20% EtOAc in hexanes.Tubes containing the product were combined and concentrated, and driedunder a high vacuum to give the product as a mixture of diastereomers.Yield: 6.8 g (42%); LCMS: (+) ESI: m/z=242 [M]⁺; ¹H NMR (300 MHz, CDCl₃,peaks corresponding to syn isomer listed) δ 7.43 (m, 2H, ArH), 7.7.14(m, 1H, ArH), 4.09 (dd, 1H, CHOH, J=12 Hz and 4.8 Hz), 3.74 (dd, 1H,CHOH, J=12 Hz and 8.4 Hz), 2.73 (bs, 1H, OH), 1.91 (m, 1H, ArCCH₂CH),1.62 (m, 2H, ArCCH ₂CH).

An oven-dried, 500 mL round-bottomed flask was charged with LAH (2.13 g,0.056 mole) and diethyl ether (210 mL). The mixture was cooled to <5° C.by ice bath, and after 10 min, a solution of carbonitrile (6.8 g, 0.028mole) in diethyl ether (90 mL) was added via addition funnel over 30 minafter which the contents were stirred at ice-bath temperature for 3 h.The reaction slurry was quenched carefully by slow addition of 25% aq.NaOH solution (5.5 mL) and stirred at ice-bath temperature for 45 min.Water (5 mL) was added and the contents filtered and washed with ether(2×50 mL). The combined filtrate was concentrated under reduced pressureand dried under a high vacuum pump overnight to afford a colorless thickliquid. Yield: 6.0 g (87%); LCMS: (+) ESI: m/z=246 [M]⁺; ¹H NMR (300MHz, CDCl₃) δ: 7.50 (d, 1H, ArH), 7.40 (d, 1H, ArH), 7.24 (dd, 1H, ArH),4.32 (dd, 1H, CHOH), 3.43 (d, 1H, CH ₂N), 3.34 (dd, 1H, CHOH), 2.60 (d,1H, CH ₂N), 1.71 (m, 1H, ArCCH₂CH), 0.94 (dd, 1H, ArCCH ₂CH), 0.77 (m,1H, ArCCH ₂CH).

Boc anhydride (5.91 g, 0.026 mole) was added in one portion to a stirredsolution of amino alcohol in anhydrous DCM (150 mL), and the reactionmixture stirred at ambient temperature under argon for 4.5 h. Water (200mL) was added to the reaction mixture and the organic layer separated.The organic layer was washed with brine (100 mL), dried (Na₂SO₄),filtered, and concentrated to give N-boc amino alcohol as a colorlessliquid that became a colorless glass upon standing. The material wasused without further purification. Yield: 9.0 g (quantitative); LCMS:(+) ESI: m/z=368 [M+Na]⁺.

PDC (23 g, 0.06 mole) was added in one portion to a stirred mixture ofN-boc amino alcohol (9.0 g, 0.026 mole) and molecular sieves (23 g) inanhydrous DCM (200 mL). The resulted dark brown reaction mixture wasstirred at ambient temperature under argon for 3.5 h. The reactionmixture was diluted with diethyl ether (50 mL), filtered through a plugof Celite® using a sintered funnel and washed with dichloromethane (3×50mL). The dark brown filtrate was concentrated to give a thick brownliquid which was purified via column chromatography using approximately250 g silica. The column was first eluted with 100% hexanes, changingthe gradient to 9:1 hexanes:EtOAc, then 8:2 hexanes:EtOAc. Tubescontaining the product were combined, concentrated, and dried on a highvacuum pump overnight to give the desired product. Yield: 4.1 g (49%);LCMS: (+) ESI: m/z=364 [M+Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.43 (d, 1H,ArH), 7.36 (d, 1H, ArH), 7.09 (dd, 1H, ArH), 4.03 (dd, 1H, CH₂N), 3.91(d, 1H, CH₂N), 2.30 (d, 1H, ArCCH₂CH), 1.60 (m, 1H, ArCCH ₂CH), 1.54 (s,9H, tert-Bu), 1.34 (m, 1H, ArCCH ₂CH).

A solution of methyl lithium-ether (3.4 mL, 5.42 mmole, 1.6M) was addeddrop wise via a syringe to a stirred solution of N-boc lactam (1.6 g,4.7 mmole) in anhydrous THF cooled at dry-ice/acetone bath temperature.The reaction mixture was stirred with cooling (<−78° C.) for 3 h andthen warmed to ambient temperature. The reaction mixture was quenchedwith 1N aq HCl solution (20 mL) and then extracted with ethyl acetate(2×20 mL). The combined organic layer was washed with brine (20 mL),dried (Na₂SO₄), filtered, and concentrated to result in a yellow liquid.The compound was purified via column chromatography on silica (˜100 g)eluting with 10% EtOAc-hexane and increasing to 20% EtOAc-hexanes. Thedesired fractions were combined, concentrated under reduced pressure,and dried to afford the desired product. Yield: 1.17 g (70%); LCMS: (+)ESI: m/z=380 [M+Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ: 7.39 (m, 2H, ArH), 7.17(dd, 1H, ArH), 4.50 (bs, 1H, NH), 3.52 (m, 2H, CH₂N), 2.42 (s, 3H, CH₃),2.30 (d, 1H, ArCCH₂CH), 1.66 (m, 1H, ArCCH ₂CH), 1.34 (s, 9H, tert-Bu),1.24 (m, 1H, ArCCH ₂CH).

The product from Example XV E above was added to methanol and stirred atambient temperature under Ar (g) in a 50 mL round-bottomed flask.Potassium borohydride was added portion-wise and the resultingsuspension stirred overnight. A clear solution was obtained. Theresulting solution was partitioned between EtOAc (10 mL) and water (10mL). The aqueous layer was extracted with EtOAc (2×10 mL) and thecombined layers washed with brine (10 mL). The organic layer was driedover sodium sulfate for 2 hours and filtered, concentrated under reducedpressure, and dried for 1 hour to afford a solid. The solid was purifiedon a filterpad of 20 g of silica eluting with 4/1 hexanes/EtOAc (v/v),switching to 1/1 hexanes/EtOAc (v/v) upon collection of the major spot.The second (desired) diastereomer was collected, including undesireddiastereomer, yield: 0.321 g, 40%; and desired diastereomer, yield:0.254 g, 32%; ¹H NMR, Undesired diastereomer: (300 MHz, CDCl₃) δ:7.34-40 (m, 2H, ArH), 7.15 (m, 1H, ArH), 4.93 (bs, 1H, NH), 3.50-61 (m,3H, CH₃), 3.25 (m, 2H, CH₂N), 1.2-1.4 (m, 9H, tert-Bu), 0.95-1.0 (m, 1H,ArCCH₂), 0.54 (m, 1H, ArCCH₂); Desired diastereomer 1-7: (300 MHz,CDCl₃) δ: 7.37 (d, 1H, J=18 Hz, ArH), 7.35 (m, 1H, ArH), 7.11 (m, 1H,ArH), 4.48 (bs, 1H, NH), 3.78 (m, 3H, CH₃), 3.57 (m, 1H, CH₂N), 3.37 (d,1H, J=5 Hz, CH₂N), 3.32 (d, 1H, J=5 Hz, CHOH), 1.4 (s, 9H, tert-Bu),1.23 (m, 1H, CH), 1.03 (m, 2H, ArCCH₂).

The compound from Example XV F above was added to DCM and triethylamineand cooled in an ice bath under Ar (g) with stirring. Methanesulfonylchloride was added dropwise with stirring over 10 min, and the resultingsuspension warmed to ambient temperature overnight. The resulting yellowsolution was washed with water (2×10 mL) and the DCM layer dried overmagnesium sulfate. The mixture was filtered and concentrated underreduced pressure to afford a yellow oil. This oil was dissolved in 0.8mL of DCM and cooled in an ice bath under Ar (g). To this was added 0.8mL of TFA and the resulting solution was stirred at ambient temperaturefor 1 hour. The solution was concentrated under reduced pressure,quenched with concentrated NaOH, and extracted with ether (2×10 mL). Theorganic extracts were combined and dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The oil was purifiedon a 2000 micron prep plate eluting with 10/1 CHCl₃MeOH (v/v) to affordthe desired free base. Yield: 0.030 g 15%; LCMS (+) ESI: m/z=242 [M+H]⁺(100); 244 [M+H]⁺ (65); UV (λ_(max)=218)=97%; ¹H NMR (300 MHz, CDCl₃) δ7.32-36 (m, 1H, ArH), 7.23-26 (m, 1H, ArH), 7.01-04 (m, 1H, ArH), 3.37(q, 1H, J=7 Hz, CHCH₃), 3.20-25 (m, 2H, CH₂N), 1.55 (m, 1H, CHCH₂), 1.22(m, 3H, CHCH₃), 0.96 (m, 2H, ArCCH₂); ¹³C NMR (75 MHz, CDCl₃) δ 130.3,129.3, 126.7, 55.7, 50.7, 32.4, 21.1, 15.8

H. Preparation of the Hydrochloride Salt of(±)-1-(3,4-dichloro-phenyl)-(r)-4-methyl-3-aza-bicyclo[3.1.0]hexane

To a vial was added 30 mg of the compound from Example XV F above, 1 mLdiethyl ether, and 0.2 mL 2N HCl in diethyl ether. A white precipitateappeared in minutes and the suspension was stirred at ambienttemperature for 1 hour. The suspension was filtered, collected, anddried to afford 18 mg of a white solid. LCMS (+) ESI: m/z=242 [MH]⁺(100); 244 [MH+2]⁺ (65); UV (λ_(max) =218)=95%; ¹H NMR (300 MHz,MeOH-d₄) δ 7.48-52 (m, 2H, ArH), 7.23-26 (m, 1H, ArH), 4.63 (s(br), 2H,NH₂) 3.93 (q, 1H, J=7 Hz, CHCH₃), 3.68 (m, 2H, CH₂N), 2.08 (dd, 1H, J=8Hz, 5 Hz, CHCH₂), 1.45 (m, 3H, CHCH₃), 1.29 (m, 1H, CH), 1.16 (m, 2H,ArCCH₂).

EXAMPLE XVI Preparation of 1-Aryl-4-methyl-3-aza-bicyclo[3.1.0]hexaneand 1-Aryl-3,4-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction Scheme22

TFA (7.5 mL, 96 mmole) was added drop wise via a syringe over a periodof 10 min to a stirred and colorless solution of N-boc lactam preparedaccording to Example XV, D above (4.1 g, 12 mmole) in anhydrous DCM (100mL) at ice-bath temperature. The resulting light brown solution wasstirred at ambient temperature for 6 h. The reaction mixture wasconcentrated and dissolved in dichloromethane (100 mL). This solutionwas washed with saturated aqueous NaHCO₃ solution (50 mL), brine (50mL), dried (Na₂SO₄), filtered, and concentrated to give an off-whitesolid. It was dried on a high vacuum pump overnight. Yield: 2.7 g (93%);LCMS: (+) ESI: m/z=242 [MH]⁺.

A solution of TMSCI (0.52 mL, 4.1 mmole) in toluene (2 mL) was addeddrop wise via syringe to a stirred suspension of lactam (0.9 g, 3.72mmole) and triethylamine (0.64 mL, 4.46 mmole) in anhydrous toluene (12mL) that was cooled in an ice-bath. The resulting white turbid solutionwas stirred at 50° C. for 4 h and then cooled in an ice-bath. Themixture was filtered through a plug of Celite eluting withhexanes:diethyl ether (1:1, 10 mL) and washed with additionalhexanes:diethyl ether (1:1, 10 mL). The combined filtrates wereconcentrated and dried under high vacuum for 30 min. The residue wasdissolved in anhydrous diethyl ether (10 mL) and cooled using adry-ice/acetone bath to a temperature of approximately −30° C. Asolution of MeLi (0.64 mL, 4.46 mmole) solution was added drop wise andcontinued stirring at −30° C. (bath temp) for 30 min. The cold bath wasremoved and the contents stirred at ambient temperature for 1 h. Thereaction mixture was quenched with addition to an aqueous ammoniumchloride solution (0.5 g in 12 mL) and the contents stirred at ambienttemperature for 30 min. The organic layer was separated, washed withbrine (25 mL), dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The oil was dried under high vacuum for 2 h to give a yellowoil. The oil was purified via chromatography on silica (100 g), firsteluting with hexanes:EtOAc (8:2), and gradually increasing the polarityto 7:3, 1:1, and finally 2:8 hexanes:EtOAc. Tubes containing the desiredproduct were combined and concentrated under reduced pressure and driedunder high vacuum overnight to afford the product. Yield: 0.6 g (71%);LCMS: (+) ESI: m/z=240 [M]⁺.

Sodium cyanoborohydride (0.24 g, 3.83 mmole) was added to a stirredsolution of imine (0.6 g, 2.5 mmole) in ethanol (8 mL). To this mixturewas added a solution of 1.2M HCl-ethanol (3.1 mL, 3.83 mmole) drop-wise.The resulting white suspension was stirred at ambient temperature for 2h. The reaction mixture was poured into a mixture of brine (30 mL) and2N aqueous NaOH solution (3 mL), and extracted with ethyl acetate (3×20mL). The combined organic layer was washed with brine (20 mL), dried(Na₂SO₄), filtered, and concentrated and dried under high vacuum to givea light yellow oil. The liquid was purified by chromatography on silica(100 g), eluting first with 1% MeOH—CHCl₃ and gradually increasing thepolarity to 2%, 3%, and finally to 5% MeOH—CHCl₃. Tubes containing thedesired product were combined, concentrated, and dried under high vacuumto afford the product as colorless liquid. Yield: 0.3 g (47%); ¹H NMR(300 MHz, CD₃OD) δ 7.35 (d, 1H, J=8.4 Hz, ArH), 7.28 (d, 1H, J=2.1 Hz,ArH), 7.06 (dd, 1H, J=8.1 Hz and 2.1 Hz, ArH), 3.42 (m, 1H, —CHCH₃),3.16 (d, 1H, J=11.4 Hz, CH₂N), 3.00 (dd, 1H, J=11.1 Hz, 0.6 Hz, CH₂N),1.73 (m, 1H, CHCH₂), 1.14 (d, 3H, J=6.3 Hz, CHCH₃), 1.01 (m, 1H,ArCCH₂), 0.76 (m, 1H, ArCCH₂); ¹³C NMR (300 MHz, CDCl₃) δ 144.94,133.26, 131.54, 130.71, 130.05, 127.95, 56.35, 53.58, 33.74, 32.82,17.36 13.02; LC-MS: (+) ESI: m/z=242 [M]⁺ (100); UV (λ_(max) =218)=100%.

A solution of HCl-ether (2.0M, 6.6 mL, 1.32 mmole) was added to astirred solution of amine (0.16 g, 0.66 mmole) in anhydrous diethylether (2 mL). The resulting white suspension was stirred at ambienttemperature for 30 min. The reaction mixture was filtered and washedwith cold anhydrous ether (5 mL) to give a bright white solid, andfurther dried to a constant mass under high vacuum. Yield: 0.172 g(94%); ¹H NMR (300 MHz, CD₃OD) δ 7.49 (m, 2H, ArH), 7.23 (dd, 1H, J=8.4Hz, 2.1 Hz, ArH), 4.18 (m, 1H, CHCH₃), 3.71 (d, 1H, J=11.7 Hz, CH₂N),3.62 (dd, 1H, J=11.7 Hz, 1.2 Hz CH₂N), 2.22 (m, 1H, CHCH₂), 1.44 (d, 3H,J=6.3 Hz, CHCH₃), 1.20 (m, 1H, ArCCH₂), 0.88 (m, 2H, ArCCH₂); LC-MS: (+)ESI: m/z=242 [M⁺] (100); UV (λ_(max) =218)=100%.

Amine (0.1 g, 0.41 mmole) and diisopropylethylamine (0.165 mL, 0.95mmole) were dissolved in anhydrous DMF (1 mL) with stirring at ambienttemperature for 30 min. Iodomethane (0.033 mL, 0.54 mmole) was added andstirring continued at ambient temperature for 20 h. The reaction mixturewas concentrated and dried under high vacuum for 1 h to give asemi-solid that was purified via chromatography on silica eluting with1% MeOH-EtOAc to afford the product as a colorless glass. Yield: 0.061 g(58%); ¹H NMR (300 MHz, CDCl₃) δ 7.40 (d, 1H, J=8.1 Hz, ArH), 7.31 (d,1H, J=2.1 Hz, ArH), 7.08 (dd, 1H, J=8.4 Hz, 2.1 Hz, ArH), 3.36 (d, 1H,J=9 Hz, CH₂N), 2.74 (m, 1H, CHCH₃), 2.71 (d, 1H, J=9 Hz, CH₂N), 2.32 (s,3H, CH₃N), 1.86 (b, 1H, ArCCH₂CH), 1.35 (m, 1H, ArCCH₂), 1.16 (d, 3H,J=6.3 Hz, CHCH₃), 0.73 (m, 1H, ArCCH₂); ¹³C NMR (300 MHz, CDCl₃) δ144.9, 133.3, 131.5, 130.7, 129.6, 127.5, 63.3, 62.9, 40.2, 32.8, 30.9,29.3, 16.3, 15.6; LC-MS: (+) ESI: m/z=256 [M]⁺ (100).

A solution of HCl-ether (2.0M, 2.2 mL, 1.32 mmole) was added to asolution of amine (0.06 g, 0.23 mmole) in anhydrous methanol (2 mL) andstirred at ambient temperature for 30 min. The reaction mixture wasconcentrated and dried under high vacuum to give an off-white solid thatwas triturated with anhydrous diethyl ether and filtered, washing withcold anhydrous ether (5 mL), and dried under high vacuum to give an offwhite solid. Yield: 0.030 g (44%); ¹H NMR (300 MHz, CD₃OD) δ 7.49 (m,2H, ArH), 7.21 (dd, 1H, ArH, J=8.1 Hz, 2.1 Hz, CHCH₃), 3.98 (m, 2H,CH₂N, CHCH₃), 3.65 (m, 1H, CH₂N), 2.93 (s, 1H, NCH₃), 2.28 (m, 1H,CHCH₂), 1.46 (d, 3H, CHCH₃, J=6.3 Hz), 1.23 (m, 1H, ArCCH₂), 0.89 (m,1H, ArCCH₂); LC-MS: (+) ESI: m/z=256 [M]⁺(100); UV (λ_(max) =218)=100%.

EXAMPLE XVII Preparation of 1-Aryl-2-methyl-3-aza-bicyclo[3.1.0]hexaneand 1-Aryl-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction Scheme23

1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione and toluenewere combined in a 500 mL round-bottomed flask and stirred under Ar (g)for 10 min while cooling in an ice bath. Red-Al® was added via additionfunnel drop-wise over several minutes. Upon complete addition, the icebath was removed and the reaction stirred at ambient temperatureovernight. The reaction mixture was cooled in an ice bath and 150 mL of5N NaOH was carefully added. The phases were separated and the aqueousphase was extracted with toluene (2×100 mL), DCM (3×100 mL), and theorganic layers combined. The organic layer was washed with brine (200mL) and dried over sodium sulfate for 8 h. The mixture was filtered,concentrated in vacuo, and dried to afford 5 g of a dark brownsemi-solid. The semi-solid was purified on a silica gel column elutingwith 20% EtOAc in hexanes increasing the polarity to 30% EtOAc andfinally 50% EtOAc. The desired fractions containing the product werecombined, concentrated, and dried to afford a light yellow solid. Yield:2.0 g 30%; LCMS (+) ESI: m/z=242 [M]⁺; m/z=264 [M+Na]⁺; ¹H NMR (300 MHz,CDCl₃) δ 7.52 (d, 1H, ArH), 7.39 (d, 1H, ArH), 7.28 (dd, 1H, ArH), 6.02(bs, 1H, NH), 3.64 (dd, 1H, NHCH₂), 3.40 (d, 1H, NHCH₂), 2.28 (m, 1H,NHCH₂CH), 1.50 (dd, 1H, ArCCH₂), 1.26 (m, 1H, ArCCH₂).

To a 50 mL, round-bottomed flask was added1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-2-one, a stir bar,triethylamine, DMAP, and DCM. The resulting brown suspension was stirredunder Ar (g), and to this was added drop-wise, a solution ofdi-tert-butyl dicarbonate in 4.1 mL of DCM over 10-15 min. Thesuspension became a solution within 1 hour and stirring continuedovernight. The solution was quenched with isopropyl amine and stirred atroom temperature for 1 hour. The organic solution was washed with 0.5NHCl (25 mL), water (25 mL), and brine (20 mL). The organic layer wasdried over magnesium sulfate for 1 hour, filtered, concentrated, anddried. The brown tar was treated with 20 mL hexanes and placed in afreezer for 24 h. The resulting solid was warmed to ambient temperatureand triturated with hexanes. The resulting powder was collected byvacuum filtration and dried under high vacuum for 24 h to afford apowder. A second crop could be collected by chromatography of thefiltrate using 4/1 hex/EtOAc. Yield: 1.21 g 43%; ¹H NMR (300 MHz, CDCl₃)δ: 7.50 (d, 1H, J=1.8 Hz, ArH), 7.39 (d, 1H, J=9.0 Hz, ArH), 7.24-28 (m,1H, ArH), 3.91 (dd, 1H, J=5.4 Hz, CHCH₂), 3.79 (d, 2H, J=9.0 Hz, CH₂N),1.45-1.58 (m, 10H, tert-Bu, ArCCH₂), 1.30 (t, 1H, J=4.8 Hz, ArCCH₂).

To a flame-dried, 10 mL round-bottomed flask was added a solution of1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acidtert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar (g). Thesolution was cooled in a dry ice/acetone bath with stirring. A solutionof MeLi was added drop-wise and the resulting orange colored mixture wasstirred at −78° C. for 3 hours. The solution was warmed to ambienttemperature and quenched with 15 mL of 1N HCl. The organic layer wasextracted with EtOAc (2×20 mL) and the combined layers washed with brine(20 mL). The organic layer was dried over sodium sulfate for 2 hours andfiltered, concentrated under reduced pressure, and dried for 1 hour toafford 1.1 g of a brown oil. The oil was purified on a filter pad ofsilica eluting with 100/1 (v/v) CHCl₃/MeOH. The desired fractions werecollected, concentrated under reduced pressure, and dried to afford ayellow oil. Yield: 0.659 g 52%; ¹H NMR (300 MHz, CDCl₃) δ 7.46 (d, 1H,J=2.1 Hz, ArH), 7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1Hz, ArH), 4.73 (m, 1H, NH), 3.41 (m, 1H, CH₂N), 3.15 (m, 1H, CH₂N), 2.04(s, 3H, CH₃), 1.80 (m, 1H, CHCH₂N), 1.45-1.58 (m, 9H, tert-Bu), 1.20(dd, 2H, J=4.5 Hz, ArCCH₂).

(±)-[2-Acetyl-2-(3,4-dichlorophenyl)-cyclopropylmethyl]-carbamic acidtert-butyl ester was added to methanol and stirred at ambienttemperature under Ar (g) in a 50 mL round-bottomed flask. Potassiumborohydride was added portion wise and the suspension stirred overnight.The resulting suspension partitioned between EtOAc (10 mL) and water (10mL). The aqueous layer was extracted with EtOAc (2×10 mL), and thecombined layers washed with brine (10 mL). The organic layer was driedover sodium sulfate for 2 hours and filtered, concentrated under reducedpressure, and dried for 1 hour to afford 0.523 g of a white stickysolid. The solid was purified on a filter pad of silica eluting with 4/1hexanes/EtOAc (v/v), switching to 6/4 hexanes/EtOAc (v/v) uponcollection of the major spot. The second (other) diastereomer wascollected. The desired compound is pale oil; Yield: 0.328 g 49%; Theundesired diastereomer is a white solid; Yield: 0.120 g 18%; ¹H NMR:Desired diastereomer: (300 MHz, DMSO-d₆) δ 7.50-53 (m, 2H, J=2.1 Hz,ArH), 7.22-25 (dd, 1H, J=9.0 Hz, J=1.8 Hz, ArH), 6.91 (bs, 1H, OH), 4.26(m, 1H, NH), 3.50 (m, 1H, CH₂N), 3.32 (m, 1H, CH₂N), 3.26 (m, 3H, CH₃),1.40 (s, 9H, tert-Bu), 1.02 (m, 2H, ArCCH₂), 0.55 (m, 1H, CHCH₂N);Undesired diastereomer (not shown): (300 MHz, CDCl₃) δ 7.57 (m, 1H,ArH), 7.50 (d, 1H, J=8.1 Hz, ArH), 7.31 (dd, 1H, J=8.4 Hz, J=1.8 Hz,ArH), 7.11 (bs, 1H, OH), 4.63 (d, 1H, J=3.3 Hz, NH), 3.46 (m, 1H), 3.33(s, 3H), 3.12 (m, 2H), 1.38 (s, 9H, tert-Bu), 1.30 (m, 1H), 0.85 (d, 2H,J=6.0 Hz, ArCCH₂), 0.78 (m, 1H, CHCH₂N)

(±)-[2-(3,4-dichlorophenyl)-(R/S)-2-(1-hydroxyethyl)-cyclopropylmethyl]-carbamicacid tert-butyl ester was added to DCM and triethylamine and cooled inan ice bath under Ar (g) with stirring. Methanesulfonyl chloride wasadded dropwise with stirring over 10 min and the resulting suspensionwarmed to ambient temperature overnight. The resulting yellow solutionwas washed with water (2×10 mL) and the DCM layer dried over magnesiumsulfate. The mixture was filtered and concentrated under reducedpressure to afford a yellow oil. This oil was dissolved in 0.8 mL of DCMand cooled in an ice bath under Ar (g). To this was added 0.8 mL of TFAand the resulting solution was stirred at ambient temperature for 1hour. The solution was concentrated under reduced pressure, quenchedwith concentrated NaOH, and extracted with ether (2×10 mL). The organicextracts were combined and dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The oil was purified on a filterpad of silica eluting with 10/1 CHCl₃/MeOH (v/v), to afford the desiredfree base. Yield: 0.065 g 30%; LCMS (+)ESI: m/z=242 [M+H]⁺ (100); UV(λ_(max)=218)=95%; ¹H NMR (300 MHz, CDCl₃) δ 7.29-32 (m, 2H, ArH), 7.06(dd, 1H, J=8.1 Hz, J=2.1 Hz, ArH), 4.36 (s, 1H, NH), 3.53 (q, 1H, J=6.6Hz, CHNH), 3.28 (dd, 1H, J=11 Hz, J=3.0 Hz, CH₂NH), 3.00 (d, 1H, J=11Hz, CH₂NH), 1.81 (q, 1H, J=4 Hz, CHCH₂), 1.01 (t, 1H, J=5 Hz, ArCCH₂),0.91 (d, 3H, J=7 Hz, CH₃), 0.68 (dd, 1H, J=8 Hz, 5.4, ArCCH₂); ¹³C NMR(75 MHz, CDCl₃) δ 140.9, 132.0, 121.2, 130.3, 130.0, 128.9, 57.6, 46.1,37.0, 22.2, 18.9, 15.6.

To prepare the hydrochloride salt, 32 mg of free base, 1 mL diethylether, and 0.2 mL 2N HCl in diethyl ether were added to a vial. A whiteprecipitate appeared in minutes and the suspension was stirred atambient temperature for 1 hour. The suspension was filtered, collected,and dried to afford 27 mg of a pale yellow solid. LCMS (+) ESI: m/z=242[M+H]⁺ (100); UV (λ_(max) =218)=95%; ¹H NMR (300 MHz, MeOH-d₄) δ: 7.60(d, 1H, J=2 Hz, ArH), 7.52 (d, 1H, J=8 Hz, ArH), 7.33 (dd, 1H, J=8 Hz,J=2 Hz, ArH), 4.16 (q, 1H, J=7 Hz, NH), 3.74 (dd, 1H, J=11 Hz, J=4 Hz,CHNH₂), 3.46 (d, 1H, J=11 Hz, CH₂NH₂), 2.34 (q, 1H, J=5 Hz, CHCH₂), 1.21(m, 1H, ArCCH₂), 1.14 (d, 3H, J=7 Hz, CH₃), 1.01 (m, 1H, ArCCH₂).

To a dried, 5 mL round-bottomed flask was added(±)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane,Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide wasadded drop wise with stirring over 5 min and the resulting solutionstirred under ambient temperature overnight. The solution wasconcentrated under reduced pressure and purified after drying. Theresidue was purified by HPLC which failed to remove the impurities. Thiswas further purified on a prep TLC plate eluting with 20/1 CHCl₃/MeOH(v/v). The desired band was collected, extracted with CHCl₃/MeOH, andconcentrated after filtration to afford the desired free base. Yield:0.005 g 15%; LCMS (+)ESI: m/z=256 [MH]⁺ (100); 258 [MH+2]⁺; (65); ¹H NMR(300 MHz, CDCl₃) δ: 7.33 (d, H, J=12 Hz, ArH), 7.32 (d, 1H, J=2 Hz,ArH), 7.08 (dd, 1H, J=9 Hz, J=2 Hz, ArH), 3.31 (q, 1H, J=6 Hz, CHNH₂),2.83 (s, 2H, CH₂N), 2.32 (s, 3H, NCH₃), 1.79 (m, 1H, CH₂CH), 1.40(t(br), 1H, ArCCH₂), 0.73 (d, 3H, J=7 Hz, CHCH₃), 0.60 (dd, 2H, J=8 Hz,4 Hz, ArCCH₂); ¹³C NMR (75 MHz, CDCl₃): δ: 131.2, 130.1, 128.9, 61.1,53.8, 36.5, 21.9, 18.4, 11.6.

EXAMPLE XVIII Preparation of 1-Aryl-2-methyl-3-aza-bicyclo[3.1.0]hexaneand 1-Aryl-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane Using Reaction Scheme24

To an oven dried, 25 mL, three-necked round-bottomed flask was added(±)-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexan-2-one,triethylamine in 6.6 mL of toluene under Ar (g) with stirring. Asolution of TMSCl in 1.1 mL of toluene was added drop wise over severalminutes. The mixture was heated at 40° C. for 4 h, then cooled to 4° C.in an ice bath, and to it was added 6.6 mL of hexanes/ether (1/1, v/v).The mixture was filtered, and the filtrate concentrated under reducedpressure and dried under high vacuum for 2 h to afford 770 mg of theintermediate that was used in the next step. A flame-dried, 10 mLround-bottomed flask was equipped with a stir bar, purged with Ar (g)and cooled to −30° C. in a dry ice/MeCN bath. The flask was charged withmethyl lithium, and to this was added a solution of the intermediate in2.85 mL of diethyl ether over 10 minutes. The resulting yellow solutionwas stirred at −20 to −25° C. for 30 minutes, followed by ambienttemperature for 1 hour. The mixture was poured into 4.9 mL of watercontaining 146 mg of ammonium chloride and stirred for 30 min. Thelayers were separated and the organic layer washed with brine (10 mL)and dried over sodium sulfate for 1 hour. The mixture was filtered,concentrated under reduced pressure, and dried under high vacuum toafford a yellow oil (488 mg). The oil was chromatographed on a filterpad of silica (12 g), eluting with 50/1 CHCl₃/MeOH (v/v). The desiredfractions were collected, concentrated, and dried to afford the desiredcompound as yellow oil. Yield: 0.409 g 52%; LCMS (+)ESI: m/z=240 [MH]⁺(100), 242 [MH+2]+(60); UV (λ_(max)=218)=95%; ¹H NMR (300 MHz, CDCl₃) δ7.40 (d, 1H, J=8 Hz, ArH), 7.35 (d, 1H, J=2 Hz, ArH), 7.10 (dd, 1H, J=8Hz, J=2 Hz, ArH), 4.09 (m, 1H, CH₂N), 3.80 (d, 1H, J=17 Hz, CH₂N), 2.09(m, 1H, CH₂CH), 1.92 (m, 3H, CH₃), 1.44 (dd, 1H, J=12 Hz, 4 Hz, ArCCH₂),0.60 (t, 1H, J=4 Hz, ArCCH₂).

To a dried, 25 mL round-bottomed flask purged with Ar (g) was addedproduct from Example XVIII A and EtOH. The mixture was stirred atambient temperature for 5 min. To this was added sodiumcyanoborohydride, followed by drop wise addition of 1.25 N HCl inethanol over 10 min. The resulting mixture was stirred at ambienttemperature for 2 hours. The solution was added to a mixture of brine/2NNaOH (20 mL/1.5 mL) and extracted with EtOAc (3×20 mL). The organiclayers were combined and washed with brine (10 mL) and dried overmagnesium sulfate for 1 hour. The mixture was filtered and the filtrateconcentrated under reduced pressure, and dried under high-vacuum toafford 435 mg of an off-white wax. The wax was purified on 20 g ofsilica (230-400 mesh), eluting with 50/1 and gradient to 10/1 CHCl₃/MeOH(v/v). Two desired sets of fractions was collected; each wasconcentrated under reduced pressure and dried under high vacuum. Topset: yellow oil, yield: 0.154 g 37%; LCMS (+)ESI: m/z=242 [MH]⁺ (100),244 [MH+2]⁺ (65); UV (λ_(max) =218)=99%; ¹H NMR (300 MHz, CDCl₃) δ: 7.36(d, H, J=5 Hz, ArH), 7.34 (d, 1H, J=1 Hz, ArH), 7.11 (dd, 1H, J=9 Hz,J=2 Hz, ArH), 3.41 (q, 1H, J=6 Hz, CH₂N), 3.17 (dd, 1H, J=12 Hz, 3 Hz,CH₂N), 2.99 (d, 1H, J=12 Hz, CHCH₃), 1.55 (m, 1H, CH₂CH), 1.08 (d, 3H,J=6 Hz, CH₃), 0.77-0.87 (m, 2H, ArCCH₂); ¹³C NMR (75 MHz, CDCl₃) δ:131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9, 18.4, 11.6; Bottom set:white solid, yield: 0.141 g 35%; LCMS (+)ESI: m/z=242 [MH]⁺ (100), 244[MH+2]⁺ (65); UV (λ_(max)=218)=99%; ¹H NMR (300 MHz, CDCl₃) δ: 7.41 (d,H, J=8 Hz, ArH), 7.36 (d, 1H, J=2 Hz, ArH), 7.12 (dd, 1H, J=9 Hz, J=2Hz, ArH), 3.75 (q, 1H, J=6 Hz, CH₂N), 3.44 (m, 1H, J=6 Hz, CH₂N), 3.33(d, 1H, J=8 Hz, CHCH₃), 1.75 (q, 1H, J=4 Hz, CH₂CH), 1.30 (d, 3H, J=3H,CH₃), 1.10 (m, 2H, ArCCH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 139.0, 132.6,131.3, 130.7, 130.6, 128.3, 60.5, 47.6, 36.0, 24.9, 14.4, 9.8.

Preparation of the Hydrochloride Salts

Top set: To a vial was added 50 mg of the yellow oil obtained from thetop set fractions as described above, 0.5 mL diethyl ether, and 0.12 mL2N HCl in diethyl ether. A white precipitate appeared in minutes and thesuspension was stirred at ambient temperature for one-half hour. Thesuspension was filtered, collected, and dried to afford 55 mg of a whitesolid.

Bottom set: To a vial was added 52 mg of the white solid obtained fromthe bottom set fractions as described above, 1.0 mL diethyl ether, and0.12 mL 2N HCl in diethyl ether. EtOH (0.5 mL) was added to obtain auniform solution. A white precipitate appeared in minutes and thesuspension was stirred at ambient temperature for one-half hour. Thesuspension was filtered, collected, and dried to afford 40 mg of a whitesolid.

LCMS Top set: (+)ESI: m/z=242 [MH]⁺ (100); 244 [MH⁺ 2]⁺ (65); UV(λ_(max)=254)=95%; Bottom set: (+)ESI: m/z=242 [MH]⁺ (100); 244 [MH⁺ 2]⁺(65); UV (λ_(max)=254)=95%

¹H NMR Top set: (300 MHz, DMSO-d₆) δ: 7.69 (d, 1H, J=2 Hz, ArH), 7.61(d, 1H, J=8 Hz, ArH), 7.33 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.00 (m, 1H,CHCH₃), 3.56 (m, 1H, CH₂N), 3.26 (m, 1H, CH₂N), 1.90 (m, 1H, CH₂CH),1.15-22 (m, 4H, CH₃, ArCCH₂), 1.01 (m, 1H, ArCCH₂); Bottom set: (300MHz, DMSO-d₆) δ: 7.69 (d, 1H, J=2 Hz, ArH), 7.61 (d, 1H, J=8 Hz, ArH),7.33 (dd, 1H, J=8 Hz, J=2 Hz, ArH), 4.00 (m, 1H, CHCH₃), 3.56 (m, 1H,CH₂N), 3.26 (m, 1H, CH₂N), 1.90 (m, 1H, CH₂CH), 1.15-22 (m, 4H, CH₃,ArCCH₂), 1.01 (m, 1H, ArCCH₂)

To an oven-dried, round-bottomed flask purged with Ar (g) was addedeither the yellow oil obtained from the top set fractions or the whitesolid obtained from the bottom set fractions as described in ExampleXVIII B above in DMF and Hunig's base. The mixture was stirred atambient temperature for 5 min. To this was added MeI, drop wise, withstirring. The resulting yellow mixture was stirred at ambienttemperature overnight. The solvent was removed via rotary-evaporationand the residue treated with 1.0 mL of 95% EtOH. The flaky whitecrystals/precipitate were collected by vacuum filtration and dried underhigh vacuum. Nature of the compound (from top set fractions): crystals,yield: 0.080 g 79%; Nature of the compound (from bottom set fractions):amorphous solid, yield: 0.042 g 40%.

LCMS

Top set: (+)ESI: m/z=256 [MH]⁺ (100), 258 [MH+2]⁺ (65); UV(λ_(max)=218)=99%; Bottom set: (+)ESI: m/z=256 [MH]⁺ (100), 258 [MH+2]⁺(65); UV (λ_(max)=218)=99%.

¹H NMR

Top set: (300 MHz, CDCl₃) δ: 7.45 (d, 1H, J=9 Hz, ArH), 7.40 (m, 1H,ArH), 7.14 (dd, 1H, J=9 Hz, J=1 Hz, ArH), 4.07 (dd, 1H, J=25 Hz, J=6 Hz,CH₂N), 3.77 (q, 2H, CH₂N, CHCH₃), 2.88 (d, 3H, J=5 Hz, NCH₃), 2.29 (m,1H, CHCH₂), 1.89 (q, 1H, J=5 Hz, ArCCH₂), 1.56-65 (m, 3H, CHCH₃), 1.24(t, 1H, J=8 Hz, ArCCH₂); Bottom set: (300 MHz, CDCl₃) δ: 7.43 (d, 1H,J=9 Hz, ArH), 7.4 (d, 1H, J=2 Hz, ArH), 7.14 (dd, 1H, J=9 Hz, J=2 Hz,ArH), 4.06 (d, 1H, J=11 Hz, CH₂N), 3.77 (m, 1H, CHCH₃), 3.30 (m, 1H,CHCH₃), 2.88 (s, 3H, NCH₃), 2.30 (m, 1H, CHCH₂), 1.88 (q, 1H, J=4 Hz,ArCCH₂), 1.63 (d, 3H, J=7 Hz, CHCH₃), 1.23 (t, 1H, J=8, ArCCH₂).

¹³C NMR

Top set: (75 MHz, MeOH-d₄) δ: 139.6, 132.4, 132.1, 130.3, 70.2, 58.8,39.6, 37.1, 23.4, 12.3, 11.3

Preparation of the Hydrochloride Salt

Bottom set: To a vial was added 47 mg of the white solid obtained fromthe bottom set fractions as described in Example XVIII B above, 1.0 mLdiethyl ether, and 0.12 mL 2N HCl in diethyl ether. EtOH (0.5 mL) wasadded to obtain a uniform solution. A yellow precipitate appeared inminutes and the suspension was stirred at ambient temperature forone-half hour. The suspension was filtered, collected, and dried toafford 40 mg of a yellow solid. LCMS Bottom set: (+)ESI: m/z=256 [MH]⁺(100), 258 [MH+2]⁺ (65); UV (λ_(max)=218)=99%; ¹H NMR Bottom set: (300MHz, MeOH-d₄) δ: 7.68 (m, 1H, ArH), 7.54 (d, 1H, J=8 Hz, ArH), 7.40 (m,1H, ArH), 3.97 (q, 1H, J=6 Hz, CH₂N), 3.76 (m, 1H, CH₂N), 2.99 (m, 3H,NCH₃), 2.0 (m, 1H, CHCH₃), 1.37 (d, 3H, J=9 Hz, CHCH₃), 1.30 (t, 1H, J=5Hz, ArCCH₂), 1.21 (m, 1H, ArCCH₂).

EXAMPLE XIX Efficacy of Exemplary Compounds of the Invention forInhibiting Monoamine Neurotransmitter Uptake

The effects of exemplary compounds of the invention on the cellularuptake of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) weretested in preparations of synaptosomes from different rat brain regionsusing the previously-reported techniques referenced below. ReferenceAssay Origin Compound Bibliography Norepinephrine (NE) Rat hypothalamusProtriptyline Perovic and Uptake synaptosomes Muller (1995) Dopamine(DA) Rat striatum GBR 12909 Janowsky et al. uptake synaptosomes (1986)5-HT uptake Rat brain Imipramine Perovic and synaptosomes Muller (1995)

Whole brains were obtained from normal rats. Synaptosomal preparationswere made from either whole brain (5-HT), striatum (DA) or hypothalamus(NE) by gentle disruption in 10 volumes (w/v) of 0.32 M sucrose (0-4°C.) using a Teflon-glass homogenizer. The homogenate was thencentrifuged at 1000×g for 10 min. The supernatant was retained andcentrifuged at 23000 g for 20 min. The resulting pellet was gentlyresuspended in 200 volumes of 0.32 M sucrose (0-4° C.) using theTeflon-glass homogenizer. Aliquots (250 μL) of this preparation wereadded to tubes, along with 0.2 μCi/mL of [³H]5-HT, [³H]DA, or [³H]NE,200 μL of the test compounds (to yield final concentrations of 100 nM,300 nM, 1 μM, 3 μM, 10 μM, 30 μM or 100 μM) and 1 mL of Krebs-Ringerbicarbonate buffer (pH 7.4). The mixtures were incubated for either 15(DA and 5-HT uptake) or 20 (NE uptake) minutes at 37° C. At the end ofthis period, the assay was terminated by rapid filtration over WhatmanGF/C glass fiber filters. The filters were rinsed 3 times with 4 ml ofKrebs-Ringer bicarbonate buffer (0-4° C.), and the radioactivityretained on the filters measured by liquid scintillation spectrometry.

Each assay was run according to the description of the respectivepublications cited above, and according to the followingparameters/reagents/conditions. Substrate/ Stimulus/ Reaction DetectionAssay Tracer Incubation Product Method NE [³H]NE 20 min. [³H]NEScintillation uptake (0.2 μCi/ml) at incorporation counting 37° C. intosynaptosomes DA [³H]DA 15 min. [³H]DA Scintillation uptake (0.2 μCi/ml)at incorporation counting 37° C. into synaptosomes 5-HT [³H]5-HT 15 min.[³H]5-HT Scintillation uptake (0.2 μCi/ml) at incorporation counting 37°C. into synaptosomes

In each experiment, the respective reference compound was testedconcurrently with the test compounds in order to assess the assaysuitability. It was tested at several concentrations (for IC₅₀ valuedetermination). The assay was considered valid if the suitabilitycriteria were met, in accordance with the corresponding StandardOperating Procedure.

The results of these uptake inhibition assays are expressed below as apercent of control values obtained in the presence of the testcompounds. Individual and mean values are presented with the results.The IC₅₀ values (concentration causing a half-maximal inhibition ofcontrol values) were determined by non-linear regression analysis of theinhibition curves using Hill equation curve fitting. TABLE 3Neurotransmitter Uptake lnhibition by 1-Aryl-3-Aza-Bicyclo[3.1.0]Hexanesof the Invention Having Multiple Substitutions on the Aryl Ring UptakeUptake Uptake IC₅₀ (nM) IC50 (nM) IC50 (nM) Binding Binding BindingStructure NE 5-HT DA NET K₁ (nM) DAT K₁ (nM) SERT K₁ (nM)

19 23 120 81 105 16

82 87 130 490 62 125

15 56 80 32 13 88

140 45 190 585 46 113

380 470 1000 1833 250 1667

550 590 1800 4000 220 2000

220 390 770 1073 170 2400

1500 1200 78 2200 240 6100

1700 3000 2200 1900 395 7600

400 2600 1200 1100 215 8900

3500 5100 8100 >10000 1100 16000

110 30 260 827 39 124

64 170 330 510 25 330

530 100 430 5150 72 132

3800 2600 1500 9500 1700 3700

650 240 1500 9300 420 800

430 1100 7400 6600

87 400 1800 990 1900 1600

210 310 1400 1700 680 230

107 186 572

86 79 770 350 640 190

41 362 494

375 835

31 252 420

25 413 437

870 520 10000 6200 NC 500

180 200 370 920 2200 540

138 266 457

91 133 401

30 110 700 260 270 830

20 836 383

54 702 917

4500 790 710

8400 4300

68 119 512

101 903

<10 65 49

56 170 98

98 31 350 520 68 6

57 <10 82

169 117 147

82 82 208

18 14 91

202 700 563

39 210 360

Readily discernable from the foregoing results is the high degree ofdiversity with respect to the biological activity changes that wereachieved by differentially altering aryl and aza substituents to yieldnovel 1-aryl-3-azabicyclo[3.1.0]hexanes according to theinvention—whereby the absolute potency at any one transporter may bealtered dramatically, and in distinct patterns among the exemplifiedcompounds. Radical changes in the potency ratio were evinced among theexemplary, multiple aryl-substituted, and combined multiple aryl- andaza-substituted, compounds. The differential potency ratios forinhibition of neurotransmitter uptake affecting dopamine, serotonin, andnorepinephrine transport yield profound and distinct therapeuticpotentials among the different, novel compounds of the invention. Boththe absolute changes in potency and the changes in potency “ratio”demonstrated herein for exemplary compounds of the invention would nothave been expected or predictable with a reasonable expectation ofsuccess by persons of ordinary skill in the art

The data provided in Table 3 demonstrate that several of the multiplearyl-substituted, and combined multiple aryl- and aza-substituted,compounds are potent (nM) inhibitors of norepinephrine and/or serotoninand/or dopamine uptake. As such, the compounds and related formulationsand methods of the invention provide neurobiologically active tools formodulating biogenic amine transport in mammalian subjects. Thesesubjects may include in vitro or ex vivo mammalian cell, cell culture,tissue culture, or organ explants, as well as human and other mammalianindividuals presenting with, or at heightened risk for developing, acentral nervous system (CNS) disorder, including neuropsychiatricdisorders such as anxiety, or depression.

In certain embodiments, neurobiologically active compositions comprisinga multiple aryl-substituted, or combined multiple aryl- andaza-substituted, 1-aryl-3-azabicyclo[3.1.0]hexane of the invention areeffective to inhibit cellular uptake of norepinephrine in a mammaliansubject. In other embodiments, these compositions will effectivelyinhibit cellular uptake of serotonin in mammals. Other compositions ofthe invention will be effective to inhibit cellular uptake of dopaminein mammalian subjects.

As illustrated by the foregoing examples, additional neurobiologicallyactive compositions of the invention will be effective to inhibitcellular uptake of multiple biogenic amine neurotransmitters inmammalian subjects, for example, norepinephrine and serotonin,norepinephrine and dopamine, or serotonin and dopamine. In additionalembodiments, the compositions of the invention are effective to inhibitcellular uptake of norepinephrine, serotonin and dopamine in mammaliansubjects.

In further-detailed embodiments, as exemplified by the results presentedin Table 3, neurobiologically active compositions of the inventionsurprisingly inhibit cellular reuptake of two, or three, biogenic aminesselected from norepinephrine, serotonin and dopamine in a mammaliansubject “non-uniformly” across an affected range of multiple biogenicamine targets. The distinct double and triple reuptake inhibitionactivity profiles demonstrated herein for exemplary compounds of theinvention illustrate the powerful and unpredictable nature of thesubject, multiple aryl-substituted, and combined multiple aryl- andaza-substituted, compounds, and further evince the ability to follow theteachings of the present disclosure to produce, select, and employ othersubstituted 1-aryl-3-azabicyclo[3.1.0]hexanes according to the inventionhaving distinct activity profiles to fulfill additional therapeutic useswithin the invention for treating diverse CNS disorders.

In exemplary embodiments, differential reuptake inhibition mediated bythe compounds of the invention may yield a profile/ratio of reuptakeinhibition activities for all three neurotransmitters, norepinephrine,dopamine, and serotonin, respectively, in reuptake inhibitionprofiles/ratios as exemplified in Table 3, selected from the followingapproximate inhibition profiles/ratios: (2:1:1); (3:10:1); (2:5:1);(12:1:5); (15:1:12); (3:8:5); (2:4:1); (3:1:2); and (2:4:1). Althoughthese values are approximate, they will correlate in a measurable waywith novel in vivo reuptake inhibition profiles/ratios as will bereadily determined by those skilled in the art.

In related embodiments, neurobiologically active compositions of theinvention inhibit cellular uptake of two, or three, biogenic amineneurotransmitters non-uniformly, for example by inhibiting uptake of atleast one member of a group of transmitters including norepinephrine,serotonin, and dopamine by a factor of two- to ten-fold greater than apotency of the same composition to inhibit uptake of one or moredifferent neurotransmitter(s). In exemplary embodiments, compositions ofthe invention comprising a multiple aryl-substituted, or combinedmultiple aryl- and aza-substituted, 1-aryl-3-azabicyclo[3.1.0]hexane,inhibit cellular uptake of serotonin by a factor of at leastapproximately two-fold, three-fold, five-fold, ten-fold or greatercompared to a potency of the same composition to inhibit uptake ofnorepinephrine, dopamine, or both norepinephrine and dopamine. In otherexemplary embodiments, different 1-aryl-3-azabicyclo[3.1.0]hexanes ofthe invention inhibit cellular uptake of dopamine by a factor of atleast approximately two-fold, three-fold, five-fold, ten-fold or greatercompared to a potency of the composition for inhibiting uptake ofnorepinephrine, serotonin, or both norepinephrine and serotonin. Inadditional exemplary embodiments, the compositions described hereininhibit cellular uptake of norepinephrine by a factor of at leastapproximately two-fold, three-fold, five-fold, ten-fold or greatercompared to a potency of the same composition for inhibiting uptake ofserotonin. In different exemplary embodiments, compositions are providedthat inhibit cellular uptake of dopamine by a factor of at leastapproximately two-fold, three-fold, five-fold, ten-fold or greatercompared to a potency of the composition for inhibiting uptake ofserotonin. In yet additional embodiments, neurobiologically activecompositions are provided that exhibit approximately equivalent potencyfor inhibiting cellular uptake of norepinephrine and serotonin, while atthe same time inhibiting dopamine uptake by a factor of at leastapproximately two-fold, three-fold, five-fold, ten-fold or greatercompared to a potency of the composition for inhibiting uptake ofnorepinephrine and serotonin. In still other exemplary embodiments,compositions of the invention exhibit approximately equivalent potencyfor inhibiting cellular uptake of serotonin and dopamine, while at thesame time inhibiting norepinephrine by a factor of no greater thanapproximately half the potency for inhibiting uptake of serotonin anddopamine. In certain embodiments, compositions of the invention exhibitapproximately equivalent potency for inhibiting cellular uptake ofnorepinephrine, serotonin, and dopamine.

Compounds of the invention that inhibit uptake of norepinephrine and/or,serotonin, and/or dopamine have a wide range of therapeutic uses,principally to treat CNS disorders, including various neuropsychiatricdisorders, as described above. Certain CNS disorders contemplated hereinwill be more responsive to a compound of the invention thatpreferentially inhibits, for example, dopamine uptake relative tonorepinephrine and/or serotonin uptake, as in the case of some forms ofdepression. Other disorders will be determined to be more responsive tocompounds of the invention that more potently inhibit norepinenephrinereuptake relative to serotonin reuptake and dopamine reuptake. Other CNSdisorders, for example, attention deficit hyperactivity disorder (ADHD),may respond better to compounds of the invention that preferentiallyinhibit dopamine and norepinephrine reuptake relative to serotoninreuptake. Thus, the host of exemplary compounds described herein, whichprovide a range of reuptake inhibition profiles/ratios, will provideuseful drug candidates for a diverse range of CNS disorders, and willeffectively treat specific disorders with lower side effect profilesthan currently available drugs.

It will be understood that the instant invention is not limited to theparticular formulations, process steps, and materials disclosed hereinas such formulations, process steps, and materials may vary somewhat. Itis also to be understood that the terminology employed herein is usedfor the purpose of describing particular embodiments only and is notintended to be limiting since the scope of the present invention will belimited only by the appended claims and equivalents thereof.

All publications and patents mentioned herein are incorporated herein byreference for the purpose of describing and disclosing, for example, theconstructs and methodologies that are described in the publications,which might be used in connection with the presently describedinvention. The publications discussed above and throughout the text areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention.

1. A compound of the following formula I:

and enantiomers and pharmaceutically acceptable salts thereof, wherein:Ar is a phenyl group substituted with two substituents independentlyselected from halogen, C₁₋₃ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl, halo(C₁₋₃)alkoxy,nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino; R₁ and R₂ areindependently selected from hydrogen, unsubstituted C₁₋₁₀ alkyl, C₃₋₁₀alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl, C₃₋₁₀ alkenyland C₃₋₁₀ alkynyl wherein the substituent is one or more of hydroxy,cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy, aryloxy,aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆ alkylindependently substituted with one or more of cyano and halogen, C₁₋₄alkoxy, and C₁₋₄ haloalkoxy; and R₃ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₃₋₈cycloalkyl, C₄₋₉cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, and substituted C₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀alkynyl wherein the substituent is one or more of cyano, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy,C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy,C₄₋₉ cycloalkanoyl, aryl, aryloxy, heteroaryl and saturatedheterocyclic; with the proviso that when the substituted phenyl group is3,4-dichlorophenyl, R₃ cannot be hydrogen.
 2. The compound according toclaim 1 wherein the phenyl group is substituted with two substituentsindependently selected from methyl, ethyl, fluoro, chloro,trifluoromethyl, cyano, nitro, and trifluoromethoxy.
 3. The compoundaccording to claim 2 wherein R₁ and R₂ are hydrogen or methyl and R₃ ishydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butylor cyclopropyl.
 4. The compound according to claim 3 selected from thegroup consisting of:1-(2,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;3-ethyl-1-(2,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane;1-(2,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(3,4-difluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(2,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(2,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;1-(2,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane;1-(4-fluoro-3-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;3-ethyl-1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane;1-(4-fluoro-3-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-methylphenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-methoxyphenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;and 1-(3-chloro-4-nitrophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts, enantiomers, polymorphs, solvates,hydrates and prodrugs thereof.
 5. The compound according to claim 4which is(1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexaneand pharmaceutically acceptable salts thereof.
 6. The compound accordingto claim 4 which is(1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexaneand pharmaceutically acceptable salts thereof.
 7. The compound accordingto claim 4 which is3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 8. Thecompound according to claim 4 which is1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 9. Thecompound according to claim 4 which is1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 10. Thecompound according to claim 4 which is(1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexaneand pharmaceutically acceptable salts thereof.
 11. The compoundaccording to claim 3 selected from the group consisting of:Cis-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane;Cis-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane;Trans-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane;Trans-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane;Cis-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane;Trans-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane;Trans-1-(3,4-dichlorophenyl)-3,4-dimethyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane;1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane;1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane;1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane;3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane;1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane;3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane;and(1S,5R)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexaneand pharmaceutically acceptable salts, enantiomers, polymorphs,solvates, hydrates and prodrugs thereof.
 12. The compound according toclaim 11 which is(1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.
 13. A compound of thefollowing formula II:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; R₃ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, and substituted C₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀alkynyl wherein the substituent is one or more of cyano, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy,C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy,C₄₋₉ cycloalkanoyl, aryl, aryloxy, heteroaryl and saturatedheterocyclic; and R₄ and R₅ are independently hydrogen or 1-4substituents independently selected from halogen, C₁₋₃ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl,C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.14. The compound according to claim 13 wherein R₄ and R₅ areindependently hydrogen or 1-4 substituents independently selected frommethyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy,ethoxy and trifluoromethoxy.
 15. The compound according to claim 14wherein R₁ and R₂ are hydrogen, R₃ is hydrogen, methyl, ethyl orisopropyl and R₄ and R₅ are independently selected from hydrogen,methyl, chloro, fluoro, propyl, methoxy and ethoxy.
 16. The compoundaccording to claim 15 selected from the group consisting of:1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane;1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane;1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; and1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane, andpharmaceutically acceptable salts, enantiomers, polymorphs, solvates,hydrates and prodrugs thereof.
 17. The compound according to claim 16which is1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 18. Thecompound according to claim 16 which is(1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.
 19. The compound according toclaim 16 which is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexaneand pharmaceutically acceptable salts thereof.
 20. The compoundaccording to claim 16 which is(1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.
 21. The compound according toclaim 16 which is(1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts thereof.
 22. The compound according toclaim 16 which is3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 23. Thecompound according to claim 16 which is3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane andpharmaceutically acceptable salts and enantiomers thereof.
 24. Acompound of the following formula III:

and enatiomers and pharmaceutically acceptable salts thereof, wherein:R₁ and R₂ are independently selected from hydrogen, unsubstituted C₁₋₁₀alkyl, C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl, and substituted C₁₋₁₀ alkyl,C₃₋₁₀ alkenyl and C₃₋₁₀ alkynyl wherein the substituent is one or moreof hydroxy, cyano, halogen, C₁₋₆ alkoxy, aryl substituted C₁₋₆ alkoxy,aryloxy, aryloxy substituted with one or more halogens, C₁₋₆ alkyl, C₁₋₆alkyl independently substituted with one or more of cyano and halogen,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy; R₃ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkanoyl, C₃₋₈ cycloalkyl, C₄₋₉cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, and substituted C₁₋₆ alkyl, C₂₋₁₀ alkenyl and C₂₋₁₀alkynyl wherein the substituent is one or more of cyano, halogen,hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, C₂₋₆ alkyloxycarbonyloxy,C₁₋₆ alkanoyl, C₁₋₆ alkanoyloxy, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyloxy,C₄₋₉ cycloalkanoyl, aryl, aryloxy, heteroaryl and saturatedheterocyclic; and R₄ and R₅ are independently hydrogen or 1-4substituents independently selected from halogen, C₁₋₃ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo(C₁₋₃)alkyl, cyano, hydroxy, C₃₋₅ cycloalkyl,C₁₋₃ alkoxy, C₁₋₃ alkoxy(C₁₋₃)alkyl, carboxy(C₁₋₃)alkyl, C₁₋₃ alkanoyl,halo(C₁₋₃)alkoxy, nitro, amino, C₁₋₃ alkylamino, and di(C₁₋₃)alkylamino.25. The compound according to claim 24 wherein R₄ and R₅ areindependently hydrogen or 1-4 substituents independently selected frommethyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy,ethoxy and trifluoromethoxy.
 26. The compound according to claim 25wherein R₁ and R₂ are hydrogen, R₃ is hydrogen, methyl, ethyl orisopropyl and R₄ and R₅ are independently selected from hydrogen,methyl, chloro, fluoro, propyl, methoxy and ethoxy.
 27. The compoundaccording to claim 26 selected from the group consisting of:1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;(1R,5S)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;(1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane;1-(1-fluoronaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane;1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; and3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane, andpharmaceutically acceptable salts, enantiomers, polymorphs, solvates,hydrates and prodrugs thereof. 28-93. (canceled)